BioDEX/raw_dataset · Datasets at Hugging Face

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{ "abstract": "A chronic dialysis patient developed persistent bacteremia as a result of infection with Enterococcus faecium. During the patient's illness, resistance to ampicillin, gentamicin, vancomycin, and teicoplanin developed. Despite arteriovenous (AV) graft removal and an extensive but inconclusive search for the source of the infection, bacteremia persisted. On autopsy, the patient was found to have had aortic-valve endocarditis. Endocarditis is a well-known complication in dialysis patients. Multidrug-resistant organisms are becoming more prevalent in hospitalized patients as well. Risk factors for the development of endocarditis in dialysis patients include catheters, AV grafts, and calcific valvular disease, all in conjunction with frequent access to the circulation. Avoidance of temporary catheter use by prompt placement of AV fistulas or grafts and consideration of their early use, the meticulous care of catheters once in place, and treatment of the nasal carriage of Staphylococcus aureus may lower the incidence of bacteremia and therefore endocarditis in dialysis patients. The removal of infected catheters and/or AV grafts if prompt clearing of the blood with antibiotics does not occur is the next step, followed by valve replacement in selected cases. The routine use of vancomycin in the dialysis population should be reevaluated in light of the development of high-level antibiotic-resistant organisms.", "affiliations": "Department of Medicine, George Washington University Medical Center, Washington, DC, USA.", "authors": "Vijayvargiya\|R\|R\|;Veis\|J H\|JH\|", "chemical_list": "D005839:Gentamicins; D002939:Ciprofloxacin; D017334:Teicoplanin; D014640:Vancomycin; D000667:Ampicillin", "country": "United States", "delete": false, "doi": "10.1681/ASN.V74536", "fulltext": null, "fulltext_license": null, "issn_linking": "1046-6673", "issue": "7(4)", "journal": "Journal of the American Society of Nephrology : JASN", "keywords": null, "medline_ta": "J Am Soc Nephrol", "mesh_terms": "D000667:Ampicillin; D016470:Bacteremia; D002939:Ciprofloxacin; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial; D016984:Enterococcus faecium; D005839:Gentamicins; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D017334:Teicoplanin; D014640:Vancomycin", "nlm_unique_id": "9013836", "other_id": null, "pages": "536-42", "pmc": null, "pmid": "8724886", "pubdate": "1996-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Antibiotic-resistant endocarditis in a hemodialysis patient.", "title_normalized": "antibiotic resistant endocarditis in a hemodialysis patient" }	[ { "companynumb": "US-PFIZER INC-2018363935", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFAZOLIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "19920116", "drugenddateformat": "102", "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "19920102", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFAZOLIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS ENTEROCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1992", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CRYOPRECIPITATED ANTIHEMOPHILIC FACTOR (HUMAN)" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "19920804", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CRYOPRECIPITATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPICILLIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202864", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS ENTEROCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1992", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DESMOPRESSIN ACETATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "19920804", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DDAVP" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "062911", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS ENTEROCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1992", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HCL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEICOPLANIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS ENTEROCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1992", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEICOPLANIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GENTAMICIN SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "062414", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS ENTEROCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1992", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENTAMICIN SULFATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESTROGENS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "19920804", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESTROGEN" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VIJAYVARGIYA, R.. ANTIBIOTIC?RESISTANT ENDOCARDITIS IN A HEMODIALYSIS PATIENT. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY: JASN. 1996?7 (4):536?542", "literaturereference_normalized": "antibiotic resistant endocarditis in a hemodialysis patient", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180913", "receivedate": "20180911", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15370669, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]
{ "abstract": "Drug interactions involving human immunodeficiency virus protease inhibitors are common due to their inhibition of the cytochrome P450 3A4 isoenzyme. We describe the case of an HIV-infected patient treated with ritonavir-boosted darunavir who developed cushingoid features following an intra-articular injection of triamcinolone acetate. We review the probable mechanism for this interaction and describe similar cases of Cushing syndrome in patients receiving concomitant ritonavir and triamcinolone.", "affiliations": "Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.", "authors": "Hall\|Jill J\|JJ\|;Hughes\|Christine A\|CA\|;Foisy\|Michelle M\|MM\|;Houston\|Stan\|S\|;Shafran\|Stephen\|S\|", "chemical_list": "D005938:Glucocorticoids; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D014221:Triamcinolone; D019438:Ritonavir; D000069454:Darunavir", "country": "England", "delete": false, "doi": "10.1177/0956462413480723", "fulltext": null, "fulltext_license": null, "issn_linking": "0956-4624", "issue": "24(9)", "journal": "International journal of STD & AIDS", "keywords": "AIDS; Cushing syndrome; HIV; HIV protease inhibitors; antiretrovirals; cobicistat; corticosteroids; drug interactions; ritonavir; toxicity; triamcinolone", "medline_ta": "Int J STD AIDS", "mesh_terms": "D003480:Cushing Syndrome; D000069454:Darunavir; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D007049:Iatrogenic Disease; D007270:Injections, Intra-Articular; D008875:Middle Aged; D019438:Ritonavir; D020069:Shoulder Pain; D013449:Sulfonamides; D016896:Treatment Outcome; D014221:Triamcinolone", "nlm_unique_id": "9007917", "other_id": null, "pages": "748-52", "pmc": null, "pmid": "23970582", "pubdate": "2013-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir.", "title_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir" }	[ { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10657", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATAZANAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATAZANAVIR PLUS RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR/EMTRICITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 2 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714614, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10661", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATAZANAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATAZANAVIR/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 2 DOSES, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MARAVIROC" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MARAVIROC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714618, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10666", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATAZANAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATAZANAVIR/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEVIRAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, STAT, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714619, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10667", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATAZANAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATAZANAVIR/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 2 DOSES, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR/EMTRICITABINE" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714610, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10659", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, STAT, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714615, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10663", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR/EMTRICITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 2 DOSES, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DARUNAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARUNAVIR/RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714613, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "A 32-year-old woman (148 cm, 59 kg, gravida 2, para 2) with quadruplet pregnancy was admitted to our hospital for the threatened preterm labor at 23 weeks and 2 days of gestation. She was treated with ritodrine, magnesium sulfate and nifedipine to maintain tocolysis. Betamethasone was administered to accelerate fetal lung maturity. After ritodrine dose was increased at 23 weeks and 5 days of gestation, she developed dyspnea with desaturation. Acute pulmonary edema was revealed on chest X-ray. The decision was made to proceed with emergency cesarean delivery. On arrival at the operating room, the blood pressure was 123/53 mmHg, heart rate 111 beats x min(-1), and oxygen saturation (SpO2) 84% with supplemental oxygen 15 l x min(-1) via a reserved face mask. Noninvasive positive pressure ventilation (NPPV) was initiated with S/T mode (FIO2 1.0, inspiratory positive airway pressure 10 cmH2O, expiratory positive airway pressure 6 cmH2O). The dyspnea was improved with her SpO2 100%. Spinal anesthesia was performed at L 34 using 2.5 ml of 0.5% bupivacaine and 100 microg morphine. Throughout the operation (operation time 44 minutes), she did not develop dyspnea under NPPV. NPPV was discontinued after the operation. Her SpO2 declined, and pulmonary edema on chest X-ray was exacerbated. She was transferred to the intensive care unit and NPPV was continued for 22 hours after the operation. She was discharged from the intensive care unit on the next day and was discharged from the hospital on the 6th postoperative day.", "affiliations": null, "authors": "Fujita\|Naoko\|N\|;Tachibana\|Kazuya\|K\|;Takeuchi\|Muneyuki\|M\|;Kinouchi\|Keiko\|K\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0021-4892", "issue": "63(5)", "journal": "Masui. The Japanese journal of anesthesiology", "keywords": null, "medline_ta": "Masui", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000767:Anesthesia, Epidural; D002585:Cesarean Section; D004630:Emergencies; D005260:Female; D006801:Humans; D011175:Positive-Pressure Respiration; D011247:Pregnancy; D011654:Pulmonary Edema", "nlm_unique_id": "0413707", "other_id": null, "pages": "557-60", "pmc": null, "pmid": "24864580", "pubdate": "2014-05", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema.", "title_normalized": "successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema" }	[ { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-144910", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TOCOLYSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, 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SUCCESSFUL PERIOPERATIVE USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION IN A PREGNANT WOMAN WITH ACUTE PULMONARY EDEMA. 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SUCCESSFUL PERIOPERATIVE USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION IN A PREGNANT WOMAN WITH ACUTE PULMONARY EDEMA. 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"17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Oxygen saturation decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Acute pulmonary oedema", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FUJITA N, TACHIBANA K, TAKEUCHI M, KINOUCHI K. SUCCESSFUL PERIOPERATIVE USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION IN A PREGNANT WOMAN WITH ACUTE PULMONARY EDEMA. MASUI. 2014;63 (5):557-560", "literaturereference_normalized": "successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20140701", "receivedate": "20140617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10242313, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]
{ "abstract": "The complexity of managing children with chronic disease has led to an increase in the use of long-term warfarin therapy. Time in therapeutic range (TTR) is the preferred method for determining efficacy and stability of warfarin management. This study aimed to determine the TTR achievement and incidence of adverse events among pediatric warfarin patients managed by an anticoagulation clinic over 12 months and to compare TTR achievement between patients self-testing (PST) at home and those monitored using routine methods. International normalized ratio (INR) results reported for 2012 for children currently having their warfarin therapy managed by a dedicated pediatric anticoagulation clinic were analyzed. Warfarin-related adverse events were recorded. A total of 164 patients were included. In total, 93 children performed PST and 71 children tested their INR at a hospital or pathology service. TTR achievement for the cohort was 67.1% (95% confidence interval, 64.4-69.7). A total of 69.2% of INR tests conducted at home were within the TTR compared with 64.3% of INR tests conducted at a hospital or pathology service (P=0.07). One major bleeding event occurred and there was 1 thrombotic episode. PST demonstrated noninferior warfarin stability compared with routine methods. Routine outcome evaluation of pediatric anticoagulation management within single institutions is necessary to confirm the success of such programs.", "affiliations": "Departments of *Nursing §Paediatrics, The University of Melbourne †Haematology Research, Murdoch Childrens Research Institute Departments of ‡Clinical Haematology ∥Nursing Research, The Royal Children's Hospital, Melbourne, Australia.", "authors": "Jones\|Sophie\|S\|;McLoughlin\|Siobhan\|S\|;Piovesan\|Dana\|D\|;Savoia\|Helen\|H\|;Monagle\|Paul\|P\|;Newall\|Fiona\|F\|", "chemical_list": "D000925:Anticoagulants; D014859:Warfarin", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000502", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "38(3)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D001777:Blood Coagulation; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019934:International Normalized Ratio; D008297:Male; D017063:Outcome Assessment, Health Care; D010044:Outpatient Clinics, Hospital; D012648:Self Care; D014859:Warfarin; D055815:Young Adult", "nlm_unique_id": "9505928", "other_id": null, "pages": "216-20", "pmc": null, "pmid": "26808370", "pubdate": "2016-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Safety and Efficacy Outcomes of Home and Hospital Warfarin Management Within a Pediatric Anticoagulation Clinic.", "title_normalized": "safety and efficacy outcomes of home and hospital warfarin management within a pediatric anticoagulation clinic" }	[ { "companynumb": "AU-MYLANLABS-2016M1019339", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "THERAPEUTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intracardiac thrombus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JONES S, MCLOUGHLIN S, PIOVESAN D, SAVOIA H, MONAGLE P, NEWALL F. SAFETY AND EFFICACY OUTCOMES OF HOME AND HOSPITAL WARFARIN MANAGEMENT WITHIN A PEDIATRIC ANTICOAGULATION CLINIC. J-PEDIATR-HEMATOL-ONCOL 2016;38(3):216-220.", "literaturereference_normalized": "safety and efficacy outcomes of home and hospital warfarin management within a pediatric anticoagulation clinic", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160511", "receivedate": "20160511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12355181, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "OBJECTIVE\nTo compare the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in less mature preterm infants.\n\n\nMETHODS\nProspective, randomised controlled study.\n\n\nMETHODS\nTertiary neonatal intensive care unit.\n\n\nMETHODS\nThe study enrolled 80 preterm infants with gestational age ≤28 weeks, birth weight <1000 g, postnatal age 48 to 96 h, and had echocardiographically confirmed significant PDA. Seventy extremely low birthweight (ELBW) preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h.\n\n\nMETHODS\nThe success rate and the safety of the drugs in ELBW preterm infants were the major outcomes.\n\n\nRESULTS\nPDA closure rate was significantly higher with oral ibuprofen (83.3% vs 61.7%) after the first course of the treatment (p=0.04). Although the primary closure rate was marginally higher in the oral ibuprofen group, the need for a second course of ibuprofen during the whole hospitalisation was similar between groups: 11 of 36 in oral versus 15 of 34 in intravenous groups (p=0.24) because of a higher reopening rate in the oral group. In addition to no increase in side effects with oral ibuprofen use, the need for postnatal steroid use for chronic lung disease was significantly lower in oral ibuprofen group (p=0.001).\n\n\nCONCLUSIONS\nOral ibuprofen is as effective as intravenous ibuprofen for PDA closure even in ELBW infants.", "affiliations": "Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. omererdeve@yahoo.com", "authors": "Erdeve\|Omer\|O\|;Yurttutan\|Sadik\|S\|;Altug\|Nahide\|N\|;Ozdemir\|Ramazan\|R\|;Gokmen\|Tulin\|T\|;Dilmen\|Ugur\|U\|;Oguz\|Serife Suna\|SS\|;Uras\|Nurdan\|N\|", "chemical_list": "D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen", "country": "England", "delete": false, "doi": "10.1136/archdischild-2011-300532", "fulltext": null, "fulltext_license": null, "issn_linking": "1359-2998", "issue": "97(4)", "journal": "Archives of disease in childhood. Fetal and neonatal edition", "keywords": null, "medline_ta": "Arch Dis Child Fetal Neonatal Ed", "mesh_terms": "D000284:Administration, Oral; D001724:Birth Weight; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D005260:Female; D005865:Gestational Age; D006801:Humans; D007052:Ibuprofen; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D015931:Intensive Care, Neonatal; D008171:Lung Diseases; D008297:Male; D016896:Treatment Outcome", "nlm_unique_id": "9501297", "other_id": null, "pages": "F279-83", "pmc": null, "pmid": "22147286", "pubdate": "2012-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": null, "title": "Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants.", "title_normalized": "oral versus intravenous ibuprofen for patent ductus arteriosus closure a randomised controlled trial in extremely low birthweight infants" }	[ { "companynumb": "TR-STRIDES ARCOLAB LIMITED-2016SP016820", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, AT 48 HOURS THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/KG, THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PATENT DUCTUS ARTERIOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, AT 24 HOURS THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERDEVE O, YURTTUTAN S, ALTUG N, OZDEMIR R, GOKMEN T, DILMEN U, OGUZ SS, URAS N.. ORAL VERSUS INTRAVENOUS IBUPROFEN FOR PATENT DUCTUS ARTERIOSUS CLOSURE: A RANDOMISED CONTROLLED TRIAL IN EXTREMELY LOW BIRTHWEIGHT INFANTS.. ARCH DIS CHILD FETAL NEONATAL ED.. 2012;97(4):F279-83", "literaturereference_normalized": "oral versus intravenous ibuprofen for patent ductus arteriosus closure a randomised controlled trial in extremely low birthweight infants", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20161103", "receivedate": "20161103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12905306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "Exposure of the fetus to indomethacin by administration of the drug to the mother may cause many side effects, including premature closure of the ductus arteriosus. Hypoxia is a predisposing factor for premature ductal closure and often occurs after maternal indomethacin therapy. We present two sets of monozygotic twins with twin-to-twin transfusion, where in utero ductal closure occurred in the donor twin while the recipient twin appeared unaffected. This selective closure of the ductus arteriosus suggests that the affected twin was predisposed to hypoxia and thus was more susceptible to ductal closure in response to indomethacin exposure.", "affiliations": "Children's Healthcare of Atlanta at Egleston, Department of Pathology, Emory University, Atlanta, Georgia 30322, USA. bshehat@emory.edu", "authors": "Shehata\|Bahig M\|BM\|;Bare\|Jessica B\|JB\|;Denton\|Tiffany D\|TD\|;Habib\|Maria N\|MN\|;Black\|Jennifer O\|JO\|", "chemical_list": "D015149:Tocolytic Agents; D007213:Indomethacin", "country": "England", "delete": false, "doi": "10.1080/15513810600908354", "fulltext": null, "fulltext_license": null, "issn_linking": "1551-3815", "issue": "25(3)", "journal": "Fetal and pediatric pathology", "keywords": null, "medline_ta": "Fetal Pediatr Pathol", "mesh_terms": "D000328:Adult; D000013:Congenital Abnormalities; D004373:Ductus Arteriosus; D017809:Fatal Outcome; D005260:Female; D005330:Fetofetal Transfusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D000860:Hypoxia; D007213:Indomethacin; D007231:Infant, Newborn; D006831:Polyhydramnios; D011247:Pregnancy; D047928:Premature Birth; D015149:Tocolytic Agents; D014430:Twins, Monozygotic", "nlm_unique_id": "101230972", "other_id": null, "pages": "151-7", "pmc": null, "pmid": "17060191", "pubdate": "2006", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Premature closure of the ductus arteriosus: variable response among monozygotic twins after in utero exposure to indomethacin.", "title_normalized": "premature closure of the ductus arteriosus variable response among monozygotic twins after in utero exposure to indomethacin" }	[ { "companynumb": "GXKR2007US02031", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TERBUTALINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE: 5 MG, Q4H", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERBUTALINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "70673", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE: 25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDOMETHACIN." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Streptococcal sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neonatal respiratory distress syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Placental transfusion syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hydrops foetalis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product administration error", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEHATA BM, BARE JB, DENTON TD, HABIB MN, BLACK JO. PREMATURE CLOSURE OF THE DUCTUS ARTERIOSUS: VARIABLE RESPONSE AMONG MONOZYGOTIC TWINS AFTER IN UTERO EXPOSURE TO INDOMETHACIN. FETAL PEDIATR PATHOL. 2006?25:151?7", "literaturereference_normalized": "premature closure of the ductus arteriosus variable response among monozygotic twins after in utero exposure to indomethacin", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200806", "receivedate": "20070309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 6267281, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder primarily caused by GATA3 haploinsufficiency and is challenging to diagnose in early childhood. We report a Japanese family with HDR syndrome and congenital choanal atresia. The 6-year-old female proband was diagnosed with epilepsy at the age of three. Under carbamazepine monotherapy, the patient presented hypoparathyroidism accompanied by severe hypocalcemia. Subsequently, renal ultrasound analysis revealed bilateral multicystic dysplastic kidneys. Because she had difficulty hearing, we sequenced GATA3 and determined that she had a c.708_709insC (p.Ser237Glnfs*66) allelic variant in exon 3. As a result, we found a family of this disease. Each family member, including her grandfather, mother, and two siblings, had HDR syndrome of varying clinical penetrance. We found a craniofacial anomaly, congenital choanal atresia, which was inherited as an autosomal dominant trait. Hypocalcemia coupled with vitamin D deficiency, triggered by carbamazepine treatment, ultimately revealed the proband's childhood- onset HDR syndrome. Pure-tone audiometry revealed different severities of deafness as well as the progression of sensory hearing loss. However, auditory brainstem response for hearing screening is probably insufficient for ascertaining HDR syndrome in the early stages of life. We presented new clinical clues to diagnose the HDR syndrome.", "affiliations": "National Hospital Organization Kyoto Medical Center, Department of Pediatrics, Kyoto, Japan. Electronic address: mkita@kyotolan.hosp.go.jp.;National Hospital Organization Kyoto Medical Center, Department of Neurology, Kyoto, Japan.;Shizuoka Prefectural Hospital Organization, Department of Medical Genetics, Shizuoka, Japan.", "authors": "Kita\|Makoto\|M\|;Kuwata\|Yasuhiro\|Y\|;Usui\|Takeshi\|T\|", "chemical_list": "D000927:Anticonvulsants; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D002220:Carbamazepine", "country": "Netherlands", "delete": false, "doi": "10.1016/j.anl.2018.10.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0385-8146", "issue": "46(5)", "journal": "Auris, nasus, larynx", "keywords": "Congenital choanal atresia; GATA binding protein 3; Hypoparathyroidism-deafness-renal dysplasia; Sensorineural hearing loss", "medline_ta": "Auris Nasus Larynx", "mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001301:Audiometry, Pure-Tone; D002220:Carbamazepine; D002648:Child; D002754:Choanal Atresia; D004827:Epilepsy; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D050990:GATA3 Transcription Factor; D000066502:Grandparents; D057895:Haploinsufficiency; D006319:Hearing Loss, Sensorineural; D006801:Humans; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009035:Mothers; D015997:Neonatal Screening; D009401:Nephrosis; D010375:Pedigree; D035781:Siblings; D014057:Tomography, X-Ray Computed; D014808:Vitamin D Deficiency", "nlm_unique_id": "7708170", "other_id": null, "pages": "808-812", "pmc": null, "pmid": "30396722", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Familial congenital choanal atresia with GATA3 associated hypoparathyroidism-deafness-renal dysplasia syndrome unidentified on auditory brainstem response.", "title_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response" }	[ { "companynumb": "JP-JUBILANT CADISTA PHARMACEUTICALS-2018JUB00475", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071940", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitamin D deficiency", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Primary hypoparathyroidism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tetany", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI T. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2018", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181126", "receivedate": "20181126", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15657169, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PHHY2018JP159384", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016608", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperphosphataemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI T. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2018?46(5):808-12", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190827", "receivedate": "20181123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15649792, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PHHY2019JP197693", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "016608", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperphosphataemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2019?46:808-12", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190827", "receivedate": "20190827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16748190, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "Zolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction. Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential, but several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal.\nA 32-year-old unmarried woman suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. She began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days the dose increased up to 100 mg per day. In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Post-ictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in the patient.\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects.", "affiliations": "Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran.;Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran.", "authors": "Hadinezhad\|Pezhman\|P\|;Hosseini\|Seyed Hamzeh\|SH\|", "chemical_list": null, "country": "Iran", "delete": false, "doi": "10.22088/cjim.12.0.376", "fulltext": "\n==== Front\nCaspian J Intern Med\nCaspian J Intern Med\nCJIM\nCaspian Journal of Internal Medicine\n2008-6164\n2008-6172\nBabol University of Medical Sciences Babol, Iran\n\n10.22088/cjim.12.0.376\nCase Report\nZolpidem withdrawal seizure in an Iranian young woman: A case presentation\nHadinezhad Pezhman MD 1\nHosseini Seyed Hamzeh MD 2\n1 Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran\n2 Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran\n Correspondence: Pezhman Hadinezhad, Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran. E-mail: pezhman.hadinezhad@gmail.com, Tel: 0098 1133203637, Fax: 0098 1133203637\n2021\n12 Suppl 2 S376S378\n3 6 2019\n8 12 2019\n30 12 2019\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground:\n\nZolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction. Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential, but several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal.\n\nCase presentation:\n\nA 32-year-old unmarried woman suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. She began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days the dose increased up to 100 mg per day. In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Post-ictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in the patient.\n\nConclusion:\n\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects.\n\nKey Words\n\nZolpidem\nWithdrawal\nSeizure\nCase report\n==== Body\npmcLong-term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short-term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life (1). Zolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction (2) and a short acting hypnotic drug belonging to imidazopyridine family (3). It produces its hypnotic effects via the GABA-A benzodiazepine receptor complex, and binds preferentially to those receptors containing the alpha-1 subunit (4, 5). Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential (6). In comparison with benzodiazepines,this mechanism is thought to reduce liability to induce dependence (7). Earlier it was considered to be a safer hypnotic than benzodiazepines due to its lesser potentiality to cause abuse (8). But several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal (9). Here we report a case of seizure related to withdrawal of zolpidem after long-term use in high dosage in Iran.\n\nCase presentation\n\nA 32-years-old unmarried woman who had no history of any medical disorder or head trauma and no family history of epilepsy suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. Since one year ago after her brother’s sudden death, she began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days, the dose increased up to 100 mg per day About 9 months later, she refers to a psychiatrist because of depression, anhedonia, fatigue, hopelessness and decreased appetite and the psychiatrist prescribed sertraline 50 mg once a day with diagnosis of major depressive disorder, the patient had taken the drugs with no problem for the past 3 months until than she was infected with herpes simplex virus and her doctor prescribed acyclovir 400 mg each 6 hours (1600 mg a day). In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Postictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. So she referred to her psychiatrist and a consultation with a neurologist had been requested by the psychiatrist. The neurological examinations were normal and EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in patient. As well as we use Naranjo scale for estimating the probability of relationship between seizure and zolpidem withdrawal, the patient score was 10, hence other etiologies or drugs either idiopathic causes were ruled out. After a series of laboratory tests and other examinations, no other etiologies could be identified in MRI. After 4 weeks follow-up, she consumed 5 mg zolpidem at bed time and she had no further seizure attacks and her postictal confusion resolved gradually 1 day after seizure occurred.\n\nDiscussion\n\nDuring the last decade, zolpidem (a non BZD hypnotic drug) was considered a new way for the treatment of patients with insomnia as it was suggested that it has the efficacy of BZDs for insomnia but without many side effects (10). It was suggested that zolpidem lacked muscle relaxant, anticonvulsant and anxiolytic properties and poor potential for abuse or dependence (11). GABA-A receptors include α1, α2, α3, α4, and α5 subunits receptors. The α1 subunit involves in sleeping mechanisms and α2 subunit contributes to anxiolytic action. BZDs have nonselective affinity to GABA-A subunits (12). A hypothesis about zolpidem withdrawal is long-term supra therapeutic doses saturation of the lower-affinity α2, α3 and α5 subunits on GABA-A receptors along with α1 subunits (13). Therefore, abrupt discontinuation of high doses would produce withdrawal symptoms such as anxiety, tremor, palpitation, or seizure (similar to BZDs withdrawal). Withdrawal symptoms of zolpidem were reported in less than 1% of subjects appearing within 48 hours of discontinuation (14). One of the probable factors associated with adverse effects of zolpidem is gender. Women have been found to have a significantly higher serum zolpidem concentration than men at equivalent dosage (15).\n\nSome studies showed that zolpidem withdrawal seizures occurred in higher doses than our case. In Haji Seyed Javadi et al.’s case presentation of a 30-year-old unmarried Iranian woman with dysthymic disorder and chronic insomnia was treated with zolpidem irregularly. She started to use zolpidem with 5mg per day irregularly since a year ago but augmented its daily dosage gradually to 100 to 150 mg per day in divided doses. After a period of 16 hours without taking zolpidem she developed a withdrawal syndrome, with generalized tonic-clonic seizures for two times. She was managed with supportive care and recovered completely (16). In our report, the patient consumed lower dose of zolpidem versus the current study. In other case presentations, Wang and et al. reported 2 cases of zolpidem withdrawal seizures and the result showed that potential of zolpidem dependence and withdrawal seizure are also present in the Asian population (17). According to these studies, gender is one of the susceptibility factors associated with adverse effects of zolpidem. Women had been found to have a significantly higher serum zolpidem concentration than men at equivalent dosage and in the end, ethnic differences have been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6 (18, 19). According to other case reports and studies and our case, zolpidem, soon after sudden discontinuation, causes withdrawal symptoms including insomnia, anxiety and epileptic attack, especially at high doses and long-term use. There have been several reports describing neuropsychiatric reactions such as visual hallucinations/sensory distortion, delirium, amnesia, sleepwalking/somnambulism, and nocturnal eating associated with zolpidem use (20). We suggest physicians to pay more attention to the potential of zolpidem to create dependence and withdrawal seizure. Besides, they should always keep its effects in their mind and subtilize during prescription of zolpidem for any patients and at any doses, especially for those with a previous history of drug or substance abuse and at high doses. However, this is a case study and it needs further studies to conclude about adverse effects of zolpidem.\n\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects. It warrants further investigation whether there is ethnic variation for the liability of zolpidem dependence. Nevertheless, worldwide clinicians should pay attention to the risk of withdrawal seizure related to this agent, especially at high doses.\n\nAcknowledgments\n\nWe are also grateful to each and every colleague of ours for their assistance and all people who moderated this paper,thus has improved the manuscript significantly.\n\nConflict of Interests:\n\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n\n1 Lahteenmaki R Neuvonen PJ Puustinen J Withdrawal from long-term use of zopiclone, zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia Basic Clin Pharmacol Toxicol 2019 124 330 40 30295409\n2 Sanger DJ Depoortere H The pharmacology and mechanism of action of zolpidem CNS Drug Rev 1998 4 323 40 29200233\n3 Aragona M Abuse, dependence, and epileptic seizures after zolpidem withdrawal: review and case report Clin Neuropharmacol 2000 23 281 3 11154097\n4 Chang CC Wang WF High-dose zolpidem withdrawal seizure in a patient with spinocerebellar ataxia Prim Care Companion CNS Disord 2011 13 10l01114\n5 Chiaro G Castelnovo A Bianco G Maffei P Manconi M Severe chronic abuse of zolpidem in refractory insomnia J Clin Sleep Med 2018 14 1257 9 29991431\n6 Holm KJ Goa KL Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia Drugs 2000 59 865 89 10804040\n7 Pitchot W Ansseau M Zolpidem dependence and withdrawal seizure Revue Med Liege 2009 64 407 8\n8 Boulanger-Rostowsky L Fayet H Benmoussa N Ferrandi J Dependence on zolpidem: a report of two cases L'Encephale 04 30 153 5\n9 Cubała WJ Landowski J Seizure following sudden zolpidem withdrawal Prog Neuropsychopharmacol Biol Psychiatry 2007 31 539 40 16950552\n10 Ohshima H Kotorii N Takii M Polysomnographic sleep disturbances due to high-dose zolpidem use: a case report J Clin Sleep Med 2018 14 1949 52 30373692\n11 Salva P Costa J Clinical pharmacokinetics and pharmacodynamics of zolpidem Therapeutic implications Clin Pharmacokinet 1995 29 142 53 8521677\n12 McKernan RM Rosahl TW Reynolds DS Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype Nature Neurosci 2000 3 587 92 10816315\n13 Liappas IA Malitas PN Dimopoulos NP Zolpidem dependence case series: possible neurobiological mechanisms and clinical management J Psychopharmacol 2003 17 131 5 12680751\n14 Toner LC Tsambiras BM Catalano G Catalano MC Cooper DS Central nervous system side effects associated with zolpidem treatment Clin Neuropharmacol 2000 23 54 8 10682233\n15 Cubała WJ Landowski J Wichowicz HM Zolpidem abuse, dependence and withdrawal syndrome: sex as susceptibility factor for adverse effects Br J Clin Pharmacol 2008 65 444 5 17875189\n16 Haji Seyed Javadi SA Hajiali F Nassiri-Asl M Zolpidem dependency and withdrawal seizure: a case report study Iranian Red Crescent Med J 2014 16 e19926\n17 Wang LJ Ree SC Chu CL Juang YY Zolpidem dependence and withdrawal seizure--report of two cases Psychiatr Danub 2011 23 76 8 21448102\n18 Anthony M Berg MJ Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I J Womens Health Gend Based Med 2002 11 601 15 12396893\n19 Afilal D Basselam MA Brakez Z Genetic polymorphism of drug-metabolizing enzymes CYP2C9 and CYP2C19 in Moroccan population Genet Test Mole Biomarkers 2017 21 298 304\n20 Inagaki T Miyaoka T Tsuji S Adverse reactions to zolpidem: case reports and a review of the literature Prim Care Companion J Clin Psychiatry 2010 12 09r00849\n\n", "fulltext_license": "CC BY", "issn_linking": "2008-6164", "issue": "12(Suppl 2)", "journal": "Caspian journal of internal medicine", "keywords": "Case report; Seizure; Withdrawal; Zolpidem", "medline_ta": "Caspian J Intern Med", "mesh_terms": null, "nlm_unique_id": "101523876", "other_id": null, "pages": "S376-S378", "pmc": null, "pmid": "34760086", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "25763219;21448102;17875189;11154097;30295409;8521677;12396893;16950552;28282224;10804040;30373692;10682233;21977371;19777922;12680751;10816315;15107718;21494350;29991431;29200233", "title": "Zolpidem withdrawal seizure in an Iranian young woman: A case presentation.", "title_normalized": "zolpidem withdrawal seizure in an iranian young woman a case presentation" }	[ { "companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-313764", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "77359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50-100 MG PER DAY, FOR MORE THAN 1 YEAR", "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "77359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, AT BED TIME", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Major depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Herpes simplex", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug withdrawal convulsions", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Hadinezhad P, Hosseini SH. Zolpidem withdrawal seizure in an Iranian young woman: A case presentation. Caspian J Intern Med. 2021;12(Suppl 2):S376-378", "literaturereference_normalized": "zolpidem withdrawal seizure in an iranian young woman a case presentation", "qualification": "1", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20211007", "receivedate": "20211007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19928088, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "IR-LUPIN PHARMACEUTICALS INC.-2021-18922", "fulfillexpeditecriteria": "2", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078970", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078970", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, QD DOSE INCREASED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Major depression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, EVERY 6 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Herpes simplex", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal convulsions", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Hadinezhad P, Hosseini SH. Zolpidem withdrawal seizure in an Iranian young woman: A case presentation. Caspian journal of internal medicine. 2021;12 (2):S376-378", "literaturereference_normalized": "zolpidem withdrawal seizure in an iranian young woman a case presentation", "qualification": "1", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20211008", "receivedate": "20211008", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19931692, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "Narcolepsy-type 1 is a neurological sleep-disorder caused by a selective loss of hypothalamic orexin/hypocretin-producing neurons whose underlying mechanism is considered to be immune-mediated. We report the case of a 16 year-old girl with excessive daytime sleepiness, hypnagogic/hypnopompic hallucinations and cataplexy, fulfilling narcolepsy-type 1 diagnostic criteria. She was HLA-DQB106:02/DQA101:02 positive. CSF analysis demonstrated positive IgG oligoclonal bands, pleocytosis and hypocretin-1 below detection limit. Other autoimmune processes were excluded, including autoimmune encephalitis. After treatment with intravenous immunoglobulins sleep-related hallucinations transiently improved for a month. This case's CSF inflammatory findings support the role of neuroinflammation in narcolepsy-type 1 development in genetically predisposed patients.", "affiliations": "Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain. Electronic address: ana.morenoestebanez@osakidetza.eus.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurophysiology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.", "authors": "Moreno-Estébanez\|Ana\|A\|;Bilbao Villabeitia\|Iker\|I\|;Echeverria Guibert\|Teresa\|T\|;Mendibe Bilbao\|Mar\|M\|;Boyero Durán\|Sabas\|S\|;Cabral Martínez\|Laura\|L\|;González-Pinto\|Tirso\|T\|;Agirre Beitia\|Garazi\|G\|;González Eizaguirre\|Amaia\|A\|;Rodríguez-Antigüedad\|Alfredo\|A\|", "chemical_list": "D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; D043025:Oligoclonal Bands", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jneuroim.2019.577111", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-5728", "issue": "339()", "journal": "Journal of neuroimmunology", "keywords": "Autoimmune diseases; Narcolepsy", "medline_ta": "J Neuroimmunol", "mesh_terms": "D000293:Adolescent; D015415:Biomarkers; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007964:Leukocytosis; D009290:Narcolepsy; D043025:Oligoclonal Bands", "nlm_unique_id": "8109498", "other_id": null, "pages": "577111", "pmc": null, "pmid": "31756639", "pubdate": "2020-02-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Positive oligoclonal bands and CSF pleocytosis in narcolepsy type 1: A case report supporting the immune-mediated hypothesis.", "title_normalized": "positive oligoclonal bands and csf pleocytosis in narcolepsy type 1 a case report supporting the immune mediated hypothesis" }	[ { "companynumb": "ES-ALLERGAN-1949918US", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NO SUSPECT ALLERGAN PRODUCT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORENO-ESTEBANEZ A, VILLABEITIA IB, GUIBERT TE, BILBAO MM, DURAN SB, RODRIGUES-ANTIGUEDAD A ET AL.. POSITIVE OLIGOCLONAL BANDS AND CSF PLEOCYTOSIS IN NARCOLEPSY TYPE 1: A CASE REPORT SUPPORTING THE IMMUNE-MEDIATED HYPOTHESIS. JOURNAL OF NEUROIMMUNOLOGY. 2019?339:1-4", "literaturereference_normalized": "positive oligoclonal bands and csf pleocytosis in narcolepsy type 1 a case report supporting the immune mediated hypothesis", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20191231", "receivedate": "20191210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17137237, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]
{ "abstract": "Portopulmonary hypertension is a rare but serious complication of portal hypertension or portosystemic shunting. Portopulmonary hypertension is an indication for liver transplantation or shunt closure. However, liver transplantation is contraindicated in patients with severe pulmonary arterial hypertension. Reported mortality rates are high in children with portopulmonary hypertension and there are scarce recommendations on its management. Our aim was to report on our real-world experience of managing portopulmonary hypertension in a specialised centre. We describe a series of 6 children with portopulmonary hypertension. Their median age at diagnosis was 13 years (range 10-15). The underlying liver conditions were cirrhosis of unknown origin (1), congenital portocaval shunts (3), biliary atresia (1), and portal vein cavernoma with surgical mesenterico-caval shunt (1). Median mean pulmonary arterial pressure was 47 mmHg (range 32-70), and median pulmonary vascular resistance was 6.6 Wood units (range 4.3-15.4). All patients except one were treated with a combination of pulmonary arterial hypertension-specific therapy (phosphodiesterase type 5 inhibitors and/or endothelin receptor antagonists and/or prostacyclin analogues). Three patients then benefited from shunt closure and the others underwent liver transplantation. Five patients showed improvement or stabilisation of pulmonary arterial hypertension with no deaths after a mean follow-up of 39 months. Based on our limited experience, early and aggressive treatment with a combination of pulmonary arterial hypertension-specific therapy significantly improves patients' haemodynamic profile and enables the performance of liver transplantation and shunt closure with satisfactory outcomes.", "affiliations": "Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland. Electronic address: Raphael.Joye@hcuge.ch.;Division of Pneumology, University Hospitals of Geneva, Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.;Swiss Pediatric Liver Center, University Center of Pediatric Surgery of Western Switzerland, Children's University Hospital, Geneva, Switzerland.;Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland; Division of Radiology, University Hospitals of Geneva, Geneva, Switzerland.;Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland; Division of Radiology, University Hospitals of Geneva, Geneva, Switzerland.;Swiss Pediatric Liver Center, Pediatric Gastroenterology, Hepatology and Nutrition Unit, Children's University Hospital, Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.", "authors": "Joye\|Raphael\|R\|;Lador\|Frédéric\|F\|;Aggoun\|Yacine\|Y\|;Farhat\|Nesrine\|N\|;Wacker\|Julie\|J\|;Wildhaber\|Barbara Elisabeth\|BE\|;Vallée\|Jean-Paul\|JP\|;Hachulla\|Anne-Lise\|AL\|;McLin\|Valérie Anne\|VA\|;Beghetti\|Maurice\|M\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jhep.2020.11.039", "fulltext": null, "fulltext_license": null, "issn_linking": "0168-8278", "issue": "74(3)", "journal": "Journal of hepatology", "keywords": "Liver transplantation; Medical treatment; Paediatrics; Portal hypertension; Portosystemic shunts; Pulmonary arterial hypertension", "medline_ta": "J Hepatol", "mesh_terms": null, "nlm_unique_id": "8503886", "other_id": null, "pages": "742-747", "pmc": null, "pmid": "33276028", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Outcome of paediatric portopulmonary hypertension in the modern management era: A case report of 6 patients.", "title_normalized": "outcome of paediatric portopulmonary hypertension in the modern management era a case report of 6 patients" }	[ { "companynumb": "CH-ASTELLAS-2021US007688", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Left ventricular end-diastolic pressure increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOYE R, LADOR F, AGGOUN Y, FARHAT N, WACKER J, WILDHABER BE ET AL. OUTCOME OF PAEDIATRIC PORTOPULMONARY HYPERTENSION IN THE MODERN MANAGEMENT ERA: A CASE REPORT OF 6 PATIENTS. JOURNAL OF HEPATOLOGY. 2021?74:742?7", "literaturereference_normalized": "outcome of paediatric portopulmonary hypertension in the modern management era a case report of 6 patients", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20210308", "receivedate": "20210308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18979533, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "Despite well-established cardiovascular benefits, statins have been associated with myopathic side effects ranging from myalgias to rhabdomyolysis and autoimmune necrotizing myositis. Statins have not been previously shown to cause myocarditis. Our case highlights this rare entity.", "affiliations": "Division of Cardiology, Department of Internal Medicine, USA.;Division of Cardiology, Department of Internal Medicine, USA.;Division of Cardiology, Department of Internal Medicine, USA.;Department of Medical Imaging, University of Arizona College of Medicine, Tucson, USA.;Division of Cardiology, Department of Internal Medicine, USA.", "authors": "Ajmal\|Muhammad\|M\|https://orcid.org/0000-0002-2463-3035;Singh\|Amitoj\|A\|;Kubba\|Saad\|S\|;Hershman\|Michelle\|M\|;Acharya\|Tushar\|T\|https://orcid.org/0000-0001-7315-8368", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/6660362", "fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/6660362\nCase Report\nStatin-Induced Triad of Autoimmune Myocarditis, Myositis, and Transaminitis\nhttps://orcid.org/0000-0002-2463-3035\nAjmal Muhammad 1\nSingh Amitoj 1\nKubba Saad 1\nHershman Michelle 2 3\nhttps://orcid.org/0000-0001-7315-8368\nAcharya Tushar tacharya@shc.arizona.edu\n1 2 3\n1Division of Cardiology, Department of Internal Medicine, USA\n2Department of Medical Imaging, University of Arizona College of Medicine, Tucson, USA\n3Banner University Medical Center, Tucson, USA\nAcademic Editor: Takatoshi Kasai\n\n2021\n8 4 2021\n2021 666036222 12 2020\n11 3 2021\n30 3 2021\nCopyright © 2021 Muhammad Ajmal et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nDespite well-established cardiovascular benefits, statins have been associated with myopathic side effects ranging from myalgias to rhabdomyolysis and autoimmune necrotizing myositis. Statins have not been previously shown to cause myocarditis. Our case highlights this rare entity.\n==== Body\n1. History of Presentation\n\nA 70-year-old male presented to the emergency department (ED) with shortness of breath and generalized body aches associated with muscle weakness in all extremities. These symptoms dated back a few months; however, there was an acute decompensation in the past 1 week which led to the hospital visit. Shortness of breath was associated with orthopnea and chest discomfort. At the time of presentation to the ED, there was severe limitation of daily activities including inability to get out of bed, stand from a sitting position, and perform personal grooming. Presenting vitals were stable (pulse 84 beats per minute, blood pressure 134/60 mmHg). Physical examination demonstrated diffuse tenderness and objective weakness in all four extremities (3/5 strength). Reflexes were intact, and there were no focal neurological deficits. Cardiorespiratory examination demonstrated bibasilar crackles, an elevated JVP, and bilateral lower extremities pitting edema. An electrocardiogram demonstrated a normal dual-chamber function with ventricular pacing and atrial sensing.\n\n2. Past Medical History\n\nThe patient had known diffuse nonobstructive coronary artery disease (CAD) (by coronary angiography). Other comorbidities included chronic kidney disease stage III and complete heart block status postdual-chamber pacemaker (implanted 1 year ago). His medications included atorvastatin 80 mg daily (6 months), metoprolol tartrate 25 mg twice daily, aspirin 81 mg, and glipizide 5 mg daily.\n\n3. Differential Diagnosis\n\nClinically, the patient had signs and symptoms of a combined skeletal (proximal muscle weakness) and myocardial insult (acute heart failure with evidence of elevated filling pressures). While statins were suspected to at least be partially responsible for the clinical presentation, a unifying pathophysiology was sought and would require further testing. Subsequently, focused laboratory testing, imaging, and eventual pathological testing were performed as described below.\n\n4. Investigations\n\nLaboratory examination revealed rhabdomyolysis with acute kidney injury, transaminitis, and myocardial injury (elevated hs-troponin and NT-pro BNP). Rheumatologic workup yielded an abnormally elevated anti-HMGCR-Ab, which was suggestive of autoimmune necrotizing myositis with moderate significance (Table 1). Skeletal muscle biopsy (gastrocnemius) confirmed necrotizing myopathy and neurogenic atrophy.\n\nMagnetic resonance imaging (MRI) of the upper and lower extremities demonstrated diffuse muscular edema in keeping with acute myositis (Figure 1). Due to myocardial injury (elevated serum hs-cTnT and NT-pro BNP), cardiac involvement was suspected. An echocardiogram and subsequently a cardiac MRI were obtained. Echocardiography demonstrated normal biventricular size and function without regional wall motion abnormalities and no significant valvular abnormalities. Cardiac MRI confirmed normal biventricular size and overall LV function as seen on the echocardiogram. On tissue characterization, myocardial T1 was significantly elevated (Figure 1(a)) in the midanterolateral and inferolateral left ventricular walls suggesting expanded extracellular compartment due to edema/inflammation or fibrosis. T2 mapping images also demonstrated mildly increased values corresponding to these same areas in keeping with myocardial edema (Figure 1). On dynamic perfusion imaging, there was a resting perfusion defect in these areas, presumably due to perivascular edema or direct vascular injury. Late gadolinium enhancement imaging was diagnostic for myocarditis and showed enhancement in a midwall distribution involving the midantero- and inferolateral walls and in an epicardial distribution in the apical anterior wall (Figures 1(d), 2, 3). Our proposed algorithm for evaluating statin-induced myocarditis is shown in Figure 4.\n\n5. Management\n\nThe initial suspicion for statin-induced myositis and rhabdomyolysis was confirmed with an elevated HMGCR antibody, abnormal MRI of extremities, and inflammatory myocyte necrosis on skeletal muscle biopsy. Atorvastatin was discontinued, and patient was resuscitated with intravenous normal saline. Close cardiac monitoring and electrolyte replacement were undertaken given acute myocarditis. Through the initial week of his hospitalization, the patient's renal function improved but neuromuscular weakness and pain continued. Once fulminant necrosis was confirmed on biopsy, given persistent skeletal weakness, immunosuppressive therapies were instituted. These included intravenous Solu-Medrol (125 mg daily × 3 days) and intravenous immunoglobulin (IVIG) (2 mg/kg IVIG × 1 dose). Despite this regimen, the patient remained clinically and chemically symptomatic (total CK and liver enzymes remained elevated). This prompted a trial of intravenous rituximab (1 g). Due to ongoing need for IV immunosuppression and slow improvement in muscle strength, the patient had a protracted hospital course lasting 4 weeks. Once clinically stable, he was discharged to a short-term rehabilitation facility. His laboratory work at discharge showed an improvement in CK (2815 U/L), AST (182 U/L), ALT (411 U/L), and ALP (172 U/L). He did not develop arrhythmias during the hospital stay.\n\n6. Discussion\n\nDespite its multiple, well-documented beneficial effects in atherosclerotic cardiovascular disease, statin use has been associated with side effects like muscle and liver injury [1, 2]. Myalgias have been commonly reported with statins but only 1 out of 10,000 patients develops objective muscle injury with CK elevation [3]. Most of these resolve spontaneously with statin cessation. In contrast, statin-induced autoimmune necrotizing myositis (ANM) is very rare but potentially life-threatening. It is diagnosed with antibodies to HMGCR and muscle necrosis on biopsy. ANM requires aggressive immunosuppression in addition to statin cessation [4–6].\n\nStatin-induced myocarditis with or without associated autoimmune necrotizing myositis has not been reported in literature before. In fact, some reports suggest that statins may be helpful in treating myocarditis and postmyocarditis dilated cardiomyopathy [7]. This beneficial effect in myocarditis and particularly autoimmune myocarditis is thought to be due to anti-inflammatory/pleotropic effects of statins and possibly mediated by inhibition of antigen-presenting cells and lymphocytes leading to quiescence of an inflammatory surge and reduction in inflammatory biomarkers [8].\n\nContrary to these reports, our case represents a rare instance where statins can act as an offender and result in autoimmune myocarditis. Myocarditis is likely mediated by direct tissue injury not too different in its pathogenesis from the necrotizing myositis of the skeletal muscle. It is hypothesized that statin-induced overexpression of HMGCAR in genetically susceptible individuals may lead to autoimmunity against HMGCAR causing muscle injury. Since injured muscles produce more HMGCAR, this may perpetuate a cycle that may not be abated by discontinuation of statin and require immunosuppression [5].\n\nReaders should familiarize themselves with this extremely rare adverse effect, especially in setting of elevated cardiac enzymes, which can be misinterpreted as acute coronary syndrome instead of myocarditis.\n\n7. Follow-Up\n\nThe patient was an outpatient in the cardiology and rheumatology clinic 4-week posthospital discharge and continued to show clinical improvement (he could now walk without support). His steroid regimen is gradually being tapered over 6 months with close rheumatologic follow-up.\n\n8. Conclusion\n\nThis is the first reported case of statin-induced myocarditis. Myocarditis in this patient is likely a part of the larger spectrum of statin-induced autoimmune necrotizing myositis, a very rare condition managed with aggressive immunosuppressants.\n\n9. Learning Objectives\n\nRecognize autoimmune necrotizing myositis and myocarditis as a rare complication of statin use\n\nDiagnosis and management of this life-threatening myopathy\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a) Bright signal intensity on T1 map showing increased extracellular compartment due to inflammation/fibrosis. (b) Bright signal intensity on T2 map corresponding to inflammation/edema. (c) Normal (yellow arrow) and abnormal (red arrow) perfusion due to vascular injury/myocardial edema in the areas corresponding to (d) late gadolinium enhancement (LGE).\n\nFigure 2 Late gadolinium enhancement (red arrows) in a midwall and epicardial distribution involving the inferolateral, anterolateral, and anterior walls consistent with myocarditis (short axis stack).\n\nFigure 3 Late gadolinium enhancement (red arrows) in a midwall and epicardial distribution involving the inferolateral, anterolateral, and anterior walls consistent with myocarditis (long axes).\n\nFigure 4 Algorithm for evaluating statin-induced myocarditis (LGE (late gadolinium enhancement)).\n\nTable 1 Laboratory findings.\n\nLaboratory\tPatient's results\tNormal value\t\nWhite blood cells\t7.3 K/mm3\t4-11 K/mm3\t\nHemoglobin\t10.7 g/dL\t13.5-17 g/dL\t\nPlatelets\t230 K/mm3\t130-450 K/mm3\t\nSodium\t141 mmol/L\t134-147 mmol/L\t\nPotassium\t5.3 mmol/L\t5.3 mmol/L\t\nChloride\t110 mmol/L\t95-108 mmol/L\t\nBicarbonate\t17 mmol/L\t>19 mmol/L\t\nBUN\t67 mg/dL\t8-25 mg/dL\t\nCreatinine\t1.8 mg/dL\t<1.5 mg/dL\t\nAnion gap\t14\t\t\nAST\t716 U/L\t<50 U/L\t\nALT\t907 U/L\t<60 U/L\t\nALP\t389 U/L\t<140 U/L\t\nhs-troponin\t1577 ng/L − >1619 ng/L − >1538 ng/L\t<11 ng/L\t\nNT-pro BNP\t2427 pg/mL\t<124 pg/mL\t\nCK\t29,200 U/L\t<355 U/L\t\nCK-MB\t525 ng/ml\t<6.7 ng/mL\t\nSerum aldolase\t130 IU/L\t<7.6 IU/L\t\nESR\t85\t<30\t\nHMGCR-Ab\t59\t<20\t\nANA\tNegative\tNegative\t\nASMA\tNegative\tNegative\t\nAnti-Jo1 antibodies\tNegative\tNegative\t\nAST: aspartate aminotransferase; ALT: alanine transaminase; ALP: alkaline phosphatase; NT-pro BNP: N-terminal probrain natriuretic peptide; CK: total creatine kinase; CK-MB: creatine kinase-myocardial band; ESR: erythrocyte sedimentation rate; HMGCR-Ab: β-hydroxy β-methylglutaryl-CoA reductase antibody; ANA: antinuclear antibodies; ASMA: antismooth muscle antibodies.\n==== Refs\n1 Grundy S. Stone M. Bailey A. L. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines Circulation 2019 139 25 e1082 e1143 10.1161/CIR.0000000000000625 2-s2.0-85068374636 30586774\n2 Lee W.-S. Kim J. Statin-induced liver and muscle toxicities Molecular & Cellular Toxicology 2019 15 1 9 17 10.1007/s13273-019-0002-3 2-s2.0-85059158989\n3 Law M. Rudnicka A. R. Statin safety: a systematic review The American Journal of Cardiology 2006 97 8A 52C 60C 10.1016/j.amjcard.2005.12.010 2-s2.0-33645881669 16581329\n4 Nazir S. Lohani S. Tachamo N. Poudel D. Donato A. Statin-associated autoimmune myopathy: a systematic review of 100 cases Journal of Clinical Rheumatology 2017 23 3 149 154 10.1097/RHU.0000000000000497 2-s2.0-85014598543 28277343\n5 Mammen A. L. Statin-associated autoimmune myopathy The New England Journal of Medicine 2016 374 7 664 669 10.1056/NEJMra1515161 2-s2.0-84959036898 26886523\n6 Sharma P. Timilsina B. Adhikari J. Parajuli P. Dhital R. Tachamo N. Statin-induced necrotizing autoimmune myopathy: an extremely rare adverse effect from statin use J Community Hosp Intern Med Perspect 2019 9 6 503 506 10.1080/20009666.2019.1702272 32002159\n7 Lazzerini P. E. Capecchi P. L. Laghi-Pasini F. Statins as a new therapeutic perspective in myocarditis and postmyocarditis dilated cardiomyopathy Cardiovascular Drugs and Therapy 2013 27 5 365 369 10.1007/s10557-013-6475-8 2-s2.0-84885186836 23832693\n8 Wu J. L. Matsui S. Zong Z. P. Amelioration of myocarditis by statin through inhibiting cross-talk between antigen presenting cells and lymphocytes in rats Journal of Molecular and Cellular Cardiology 2008 44 6 1023 1031 10.1016/j.yjmcc.2008.03.016 2-s2.0-44649111169 18471827\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2021()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "6660362", "pmc": null, "pmid": "33898067", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "23832693;32002159;28277343;26886523;16581329;18471827;30586774", "title": "Statin-Induced Triad of Autoimmune Myocarditis, Myositis, and Transaminitis.", "title_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis" }	[ { "companynumb": "US-TEVA-2021-US-1912434", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { 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"AJMAL M, SINGH A, KUBBA S, HERSHMAN M AND ACHARYA T.. STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. 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STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REPORTS IN CARDIOLOGY.. 2021?10.1155/2021/6660362", "literaturereference_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210519", "receivedate": "20210519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19275846, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-ACCORD-225522", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": "1", "drugadministrationroute": 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"drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Autoimmune myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiac failure acute", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Autoimmune myocarditis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrotising myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Left ventricular end-diastolic pressure increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AJMAL M, SINGH A, KUBBA S, HERSHMAN M, ACHARYA T. STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REPORTS IN CARDIOLOGY. 2021?ARTICLE NUMBER 6660362:2021. DOI: 10.1155/2021/6660362.", "literaturereference_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210524", "receivedate": "20210524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19294582, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-MICRO LABS LIMITED-ML2021-01593", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": null, "drugadministrationroute": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrotising myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Autoimmune myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiac failure acute", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Left ventricular end-diastolic pressure increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Autoimmune myocarditis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AJMAL M, SINGH A, KUBBA S, HERSHMAN M, ACHARYA T. STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REPORTS IN CARDIOLOGY. 2021?.", "literaturereference_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210521", "receivedate": "20210521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19287005, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Acute generalized exanthamous pustulosis (AGEP)is a rare eruption of non-follicular sterile pustuleson a diffuse background of erythema and edema,commonly associated with fever and leukocytosis.Antibiotics are implicated in most cases; however,other drugs have been reported to cause AGEP. Wereport a case of a 73-year-old man with a historyof ulcerative colitis who presented with a diffusepustular rash, renal failure, elevated liver functiontests, and leukocytosis with neutrophilia. A week priorto admission, the patient was started on mesalamineto treat colitis. Upon admission, a workup includinga skin biopsy was performed and was consistentwith AGEP. Mesalamine was discontinued, and thepatient's skin eruption, renal function, liver functiontests, and leukocytosis subsequently improved.Mesalamine has an unknown mechanism of action.However, it is thought to be an anti-inflammatoryagent that blocks the production of leukotrienesand prostaglandins and is an immunosuppressantthat increases the release of adenosine, whichinterferes with leukocyte function. The decrease inprostaglandin synthesis or deregulation of leukocytefunction caused by mesalamine may be the etiologyin this case. Discontinuation of the offending agentleads to resolution of AGEP, as it did in this patient.", "affiliations": "Skin Institute of South Florida, Coral Springs, Florida. kyunghwamd@ gmail.com.", "authors": "Rocci\|Erin\|E\|;Park\|Kelly\|K\|;Hutchens\|Kelli\|K\|;Winterfield\|Laura\|L\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2108", "issue": "23(1)", "journal": "Dermatology online journal", "keywords": null, "medline_ta": "Dermatol Online J", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D006801:Humans; D008297:Male; D019804:Mesalamine", "nlm_unique_id": "9610776", "other_id": null, "pages": null, "pmc": null, "pmid": "28329471", "pubdate": "2017-01-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "First report of mesalamine (5-aminosalicylic acid) as the causative agent in a case of acute generalized exanthamous pustulosis.", "title_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis" }	[ { "companynumb": "US-G+W LABS-GW2017US000088", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "076841", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "RECTAL SUSPENSION", "drugdosagetext": "4 G PER DAY (SUPPOSITORY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "076841", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "RECTAL SUSPENSION", "drugdosagetext": "UNK (SUPPOSITORY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "076841", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "RECTAL SUSPENSION", "drugdosagetext": "4.8 G PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.8", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "076841", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "RECTAL SUSPENSION", "drugdosagetext": "UNK (ONE ENEMA)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dermatitis contact", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mouth ulceration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROCCI E, PARK K, HUTCHENS K, WINTERFIELD L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. DERMATOLOGY ONLINE JOURNAL. 2016;23(1):7", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170309", "receivedate": "20170309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13312984, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-MEDA-2016060114", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.8 GRAMS PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.8", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "019618", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUPPOSITORY", "drugdosagetext": "4 GRAMS PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROCCI E,PARK, MD, MS K,HUTCHENS, MD K,WINTERFIELD, MD, MPH L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2016; 74(1): 1-4{BR}ROCCI, BS E,PARK, MD, MSL K,HUTCHENS, MD K,WINTERFIELD, MD, MPH L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. DERMATOLOGY ONLINE JOURNAL 2017; 23(1):7: 1-4", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170323", "receivedate": "20160708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12541285, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-BAUSCH-BL-2016-013974", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "022301", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUPPOSITORY", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROCCI E, PARK K, HUTCHENS K, WINTERFIELD L. FIRST REPORT OF MESALAMINE (5?AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 2016 MAY?74:5 (SUPPL 1):.", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210217", "receivedate": "20160613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12462021, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-MYLANLABS-2016M1026192", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "204354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.8 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.8", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "204354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAZINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Liver function test increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ROCCI E, PARK K, HUTCHENS K, WINTERFIELD L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. DERMATOLOGY ONLINE JOURNAL 23: NO. 1 JANUARY 2017", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170314", "receivedate": "20160624", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12497351, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]
{ "abstract": "Tuberculosis (TB) is still considered a major global public health problem in the world and there is a concern about the worldwide increase of drug-resistance (DR). This paper describes the analysis of three Mycobacterium tuberculosis isolates from a single patient collected over a long treatment period of time. DR was initially investigated through phenotypic testing, followed by line probe assays (LPAs) and whole genome sequencing (WGS). It presents an intriguing situation where a multidrug-resistant (MDR-) TB case was diagnosed and treated based only on late phenotypic drug susceptibility testing of isolate 1. During the treatment, another two isolates were cultivated: isolate 2, nine months after starting MDR-TB treatment; and isolate 3, cultivated five months later, during regular use of anti-TB drugs. These two isolates were evaluated using molecular LPA and WGS, retrospectively. All mutations detected by LPA were also detected in the WGS, including conversion from fluoroquinolones susceptibility to resistance from isolate 2 to isolate 3. WGS showed additional mutations, including some which may confer resistance to other drugs not tested (terizidone/cycloserine) and mutations with no correspondent resistance in drug susceptibility testing (streptomycin and second-line injectable drugs).", "affiliations": "Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.;Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil. Electronic address: vbollela@gmail.com.", "authors": "Silva Feliciano\|Cinara\|C\|;Rodrigues Plaça\|Jessica\|J\|;Peronni\|Kamila\|K\|;Araújo Silva\|Wilson\|W\|;Roberto Bollela\|Valdes\|V\|", "chemical_list": "D000995:Antitubercular Agents; D001426:Bacterial Proteins", "country": "Brazil", "delete": false, "doi": null, "fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(16)30036-8\n10.1016/j.bjid.2016.01.004\nBrief Communication\nEvaluation of resistance acquisition during tuberculosis treatment using whole genome sequencing\nSilva Feliciano Cinara a\nRodrigues Plaça Jessica c\nPeronni Kamila bc\nAraújo Silva Wilson Jr bc\nRoberto Bollela Valdes vbollela@gmail.com\nac⁎\na Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil\nb Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil\nc Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil\n⁎ Corresponding author. vbollela@gmail.com\n20 3 2016\nMay-Jun 2016\n20 3 2016\n20 3 290293\n28 10 2015\n5 1 2016\n© 2016 Elsevier Editora Ltda.\n2016\nElsevier Editora Ltda.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nTuberculosis (TB) is still considered a major global public health problem in the world and there is a concern about the worldwide increase of drug-resistance (DR). This paper describes the analysis of three Mycobacterium tuberculosis isolates from a single patient collected over a long treatment period of time. DR was initially investigated through phenotypic testing, followed by line probe assays (LPAs) and whole genome sequencing (WGS). It presents an intriguing situation where a multidrug-resistant (MDR-) TB case was diagnosed and treated based only on late phenotypic drug susceptibility testing of isolate 1. During the treatment, another two isolates were cultivated: isolate 2, nine months after starting MDR-TB treatment; and isolate 3, cultivated five months later, during regular use of anti-TB drugs. These two isolates were evaluated using molecular LPA and WGS, retrospectively. All mutations detected by LPA were also detected in the WGS, including conversion from fluoroquinolones susceptibility to resistance from isolate 2 to isolate 3. WGS showed additional mutations, including some which may confer resistance to other drugs not tested (terizidone/cycloserine) and mutations with no correspondent resistance in drug susceptibility testing (streptomycin and second-line injectable drugs).\n\nKeywords\n\nTuberculosis\nDrug resistant tuberculosis\nDrug susceptibility tests\nWhole genome sequencing\n==== Body\npmcTuberculosis (TB) is still considered a major global public health problem, and Brazil is the 16th country in absolute number of cases. Despite consistent advances achieved with control measures, there are still major challenges to face the growing resistance to anti-tuberculosis drugs in several countries, including Brazil.1 Molecular epidemiology studies of M. tuberculosis have gained emphasis among clinical researchers. New knowledge on the TB pathogenesis and its causative agent could be the key to the development of new control strategies.2, 3 Recently, the World Health Organization set the Global “Stop TB Plan” to find patients harboring resistant strains of M. tuberculosis. This initiative has been important to test first-line TB drugs and promoting research to develop new drugs, vaccines, and diagnostic strategies.1, 4\n\nAmong the techniques used, whole genomic sequencing (WGS) is worth mentioning, especially for the investigation of bacilli resistance. This approach enables accurate assessment of mutations related to bacilli resistance to several TB drugs. This information would allow the development of new diagnostic methods and therapeutic strategies applied for disease control.5\n\nOuthred et al. advocate the use of WGS for all multidrug-resistant M. tuberculosis isolates as an alternative plan to improve patient care, monitor for transmission events, and contribute to better understanding of resistance-associated mutations.6\n\nThis study describes a challenging case of treatment failure of a patient under MDR-TB therapy and reports phenotypic and molecular drug resistance test results in correlation to mutations identified with a whole genome sequencing analysis.\n\nThree isolates of M. tuberculosis from a single patient, during different time points of his treatment, were evaluated based on phenotyping and genotyping testing: isolate 1 was collected before the patient started the follow-up in the reference center, when clinical and microbiological failure was diagnosed, despite regular TB treatment with rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E); isolate 2 was collected in the ninth month of MDR-TB treatment (other clinical and microbiological failure); and isolate 3 was obtained on the 13th month of MDR-TB treatment.\n\nA nonradiometric phenotypic susceptibility testing was performed in liquid medium (MGIT 960; Becton Dickinson Diagnostic Systems, Sparks, MD) for isolate 1. Besides this susceptibility phenotypic testing, two line probe assays (LPA), Genotype MTBDRplus and MTBDRsl (Hain Lifescience, GmbH, Germany), were performed in isolates 2 and 3. Genotype MTBDRplus evaluates the main mutations associated with rifampicin (rpoB gene mutations) and isoniazid (katG e inhA mutations) resistance. Genotype MTBDRsl detects mutations related with resistance to fluoroquinolones (gyrA gene mutations), second-line injectable drugs (SLID) (rrs gene mutations) and ethambutol (embB gene mutations).7, 8 Finally, the two stored samples (isolates 2 and 3) were submitted to WGS analysis using Illumina MiSeq Sequecing System (Illumina, San Diego, CA, USA). LPAs and WGS tests were performed with stored isolates 2 and 3 at the end of the patient's treatment. Therefore, this information was not available to the clinician during the treatment. Isolate 1 was not tested again because it was not viable.\n\nGenerated reads with phred scale score superior to 30 was mapped with BWA v0.7.5a program (Burrows-Wheeler Alignment Tool) using the reference genome M. tuberculosis H37Rv. Conversion from sequence alignment map format to sorted, indexed BAM files was done using SAMtools (version 0.1.19). PCR-duplicates were removed using the MarkDuplicates option of the Picard software tools (version 1.61). The variants were found according to the pipeline SAMtools/BCFtools v 0.1.18 and annotated with SnpEff v 4.0. Databases TB Drug Resistance Mutation Database9 and M. tb Drug Resistance Directed Sequencing Database10 were used to identify mutations described for the TB bacilli. All detected mutations were confirmed based on TB profiler online tool, described by Coll et al.,11 to remove single nucleotide polymorphisms (SNPs) at drug resistance loci which were historically misclassified as drug resistance markers.\n\nThis project was approved by the Ethics and Research Committee of the Hospital of the Ribeirão Preto Medical School of the University of São Paulo (protocol number: 944117 – February 1, 2015).\n\nThe patient was initially treated with RHZE for six months. During the last month clinical and microbiological failure (acid-fast smear positive and respiratory symptoms) was diagnosed. This M. tuberculosis isolate showed R and H resistance in the first phenotypic susceptibility testing. The patient was referred to the regional TB drug resistance center and his treatment was switched to streptomycin (Sm), E, ofloxacin (FQ), Z, and terizidone (Tz), following the Brazilian guidelines for the management of MDR-TB. During the first nine months of treatment, there was a transient improvement followed by recurrence of symptoms. Sputum culture was collected and the same MDR-TB treatment was maintained until the 13th month. The therapy was empirically optimized by adding ethionamide, extending the period of streptomycin and increasing the local support for directly observed treatment, while the results of phenotypic testing from isolate 3 were still pending. The treatment was successfully completed after 24 months, with clinical and microbiological cure. After that, instigated by this unusual and intriguing case and its outcome, we decided to carry on molecular studies on the patient's isolates 2 and 3.\n\nIsolate 1 showed resistance to R and H in the phenotypic test. Phenotypic testing of isolate 2 showed resistance to these two drugs and also to Z. The LPA of this isolate showed resistance to R (lost wild type 8 and gained rpoB S450L mutation), H (lost wild type and gained KatG S315T1 mutation), and E (lost wild type 1 and gained embB M306V mutation). Isolate 3 showed resistance to R, I, E (same mutations described in isolate 2), and acquired a new resistance pattern to FQ (gyrA D94G mutation) in the LPA test. Phenotypic testing of isolate 3, which became available close to the end of the patient's treatment, showed resistance to the above mentioned drugs and also to Z. The critical concentrations of Bactec-MGIT 960™ reported by the manufacturer's drug susceptibility testing (DST) protocol were as follows: H: 0.10 μg/mL; R: 1.0 μg/mL; EM: 5.0 μg/mL; Sm: 1.0 μg/mL; Z: 100 μg/mL; FQ (ofloxacin): 2 μg/mL; Amikacin 1.0 μg/mL; Capreomycin 2.5 μg/mL. The susceptibility profile of isolates in the phenotypic test and LPA are described in Table 1.Table 1 Results of phenotypic and LPA tests: susceptibility profile of tested drugs.\n\nTable 1\tIsolate 1 detected resistance\tIsolate 2 detected resistance\tIsolate 3 detected resistance\t\nPhenotypic drug susceptibility testing (DST)\tRifampicin; Isoniazida\tRifampicin; Isoniazid;\tRifampicin; Isoniazid\t\n\t\tPyrazinamideb\tOfloxacin; Pyrazinamide\t\n\t\t\tEthambutolc\t\n\n\n\t\nGenotype MTBDRplus (R; H)\tNA\tRifampicin\tRifampicin\t\n\t\tIsoniazid\tIsoniazid\t\n\n\n\t\nGenotype MTBDRsl (E; FQ; SLID)\tNA\tEthambutol\tEthambutol\t\n\t\t\tFQ\t\n\n\n\t\nWGS\tNA\tAvailable (see Table 2)\tAvailable (see Table 2)\t\nNA, not available; R, rifampicin; H, isoniazid; E, ethambutol; FQ, fluoroquinolones; SLID, second line injectable drugs.\n\na Isolate 1 collected before MDR-TB treatment – susceptible to E and Sm. SLID not tested.\n\nb Isolate 2 collected in the ninth month of MDR-TB treatment – susceptible to E, SLID and FQ.\n\nc Isolate 3 collected on the 13th month of MDR-TB treatment – susceptible to Sm and SLID.\n\nThe WGS analysis of these two strains generated the total of 43,036,497 reads (28,171,267 for strain 1 and 14,865,230 for strain 2), with an average coverage of 469× for the isolate 2 and 244× for the isolate 3. Bioinformatics analysis reported 11 mutations already described as associated with resistance in isolate 2 and 12 mutations in isolate 3 (Table 2). Additional mutation in gyrA gene (D94G) was identified in isolate 3, which is one of the most frequent mutations associated with resistance to FQ, and is tested by the LPA Genotype MTBDRsl. Although all mutations showed by LPA were validated by WGS, additional mutations were detected, including those conferring resistance to other drugs despite bacilli susceptibility demonstrated in the phenotypic drug susceptibility testing (gyrA E21Q in isolate 2, rpsL promoter gene in genomic position 781395, tlyA L11L for isolates 2 and 3).Table 2 Whole genomic sequencing mutations identified in isolates 2 and 3.\n\nTable 2Gene\tAssociated drug\tGenomic position\tMutation\tStrain 2 mutation\tStrain 3 mutation\tReference allele\tMutated allele\tVariant type\t\ngyrA\tFluoroquinolones\t7362\tE21Q\tYes\tYes\tG\tC\tMissense\t\ngyrA\tFluoroquinolones\t7582\tD94Ga\tNo\tYes\tA\tG\tMissense\t\nrpoB\tRifampicin\t759939\tP45T\tYes\tYes\tC\tA\tMissense\t\nrpoB\tRifampicin\t761155\tS450L\tYes\tYes\tC\tT\tMissense\t\nrpsL\tStreptomycin\t781395\t–\tYes\tYes\tT\tC\tPromoter gene\t\ntlyA\tAminoglycosides\t1917972\tL11L\tYes\tYes\tA\tG\tSynonymous\t\nkatG\tIsoniazid\t2154915\tE399E\tYes\tYes\tA\tG\tSynonymous\t\nkatG\tIsoniazid\t2155168\tS315T\tYes\tYes\tG\tC\tMissense\t\npncA\tPyrazinamide\t2289039\tW68L\tYes\tYes\tG\tT\tMissense\t\nalr\tCycloserine\t3840719\tL234L\tYes\tYes\tA\tG\tSynonymous\t\nalr\tCycloserine\t3841403\tE6D\tYes\tYes\tG\tT\tMissense\t\nembB\tEthambutol\t4247429\tM306V\tYes\tYes\tA\tG\tMissense\t\na Mutation detected only in the isolate 3, by whole genomic sequencing.\n\nExcept for mutation D94G, the SNPs reads for isolate 2 and 3 were 100% identical, with no signs of heteroresistance.\n\nThe relation between genome mutations and phenotypic resistance is particularly important for therapeutic decision, because different mutations can cause different resistance profiles or not even cause any phenotypic resistance.12 Coll et al. compiled a library of mutations predictive of drug resistance, and removed phylogenetic SNPs at drug resistance loci, which were historically misclassified as drug resistance markers.11\n\nWGS has great application potential to detect bacilli resistance in clinical practice. However, further work is needed to determine additional resistance polymorphisms as it should be noted that high positive predictive values are crucial for drug resistance tests where the consequence of a false positive result may lead to unnecessary treatment and prolonged patient isolation.11\n\nThe WGS of M. tuberculosis is a great advance in the knowledge of bacilli resistance, as well as in the clinical management of TB. This technique presents greater discriminatory power, enabling analysis of additional mutations, not possible to be assessed by other methods. WGS has the potential for clinical use, as mentioned by other authors6, 11, 12, 13, 14 for fast and accurate assessments in cases of illness caused by strains resistant to multiple drugs, with an impact on therapeutic decisions. However, this is a high-cost technology and it is still critical to understand and standardize correlations between genotypic and phenotypic resistance to really optimize its clinical use.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 World Health Organization (WHO) Global tuberculosis report 2014 2014 World Health Organization Geneva\n2 Gomes H.M. Elias A.R. Oelemann M.A.C. Spoligotypes of Mycobacterium tuberculosis complex isolates from patients residents of 11 states of Brazil Infect Genet Evol 12 4 2012 649 656 10.1016/j.meegid.2011.08.027 Epub 2011 Sep 1 21907830\n3 García De Viedma D. Mokrousov I. Rastogi N. Innovations in the molecular epidemiology of tuberculosis Enferm Infecc Microbiol Clin 29 Suppl 1 2011 8 13 10.1016/S0213-005X(11)70012-X\n4 World Health Organization (WHO) The global plan to stop TB 2011–2015 2010 World Health Organization Geneva\n5 Ilina E.N. Shitikov E.A. Ikryannikova L.N. Comparative genomic analysis of Mycobacterium tuberculosis drug resistant strains from Russia PLoS One 8 2013 e56577 23437175\n6 Outhred A.C. Jefs P. Suliman B. Added value of whole genome sequencing for management of highly drug-resistant TB J Antimicrob Chemother 70 4 2015 1198 1202 25492392\n7 World Health Organization (WHO) Molecular line probe assays for rapid screening of patients at risk of multi-drug resistant tuberculosis (MDR-TB) 2008 World Health Organization Geneva\n8 Brossier F. Veziris N. Aubry A. Detection by genotype MTBDRsl test of complex mechanisms of resistance to second-line drugs and ethambutol in multidrug-resistant Mycobacterium tuberculosis complex isolates J Clin Microbiol 48 2010 1683 1689 20335420\n9 Sandgren A. Strong M. Muthukrishnan P. Tuberculosis drug resistance mutation database PLoS Med 6 2009 e2 19209951\n10 Broad Institute. Available at: http://www.broadinstitute.org/annotation/genome/mtb_drug_resistance.1/MultiHome.htm.\n11 Coll F. McNerney R. Preston M.D. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences Genome Med 7 2015 51 26019726\n12 Witney A.A. Gould K.A. Arnold A. Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases J Clin Microbiol 53 2015 1473 1483 25673793\n13 Liu F. Hu Y. Wang Q. Comparative genomic analysis of Mycobacterium tuberculosis clinical isolates BMC Genomics 15 2014 469 24923884\n14 Clark T.G. Mallard K. Cell F. Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing PLoS One 8 2013 e83012 24349420\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1413-8670", "issue": "20(3)", "journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases", "keywords": "Drug resistant tuberculosis; Drug susceptibility tests; Tuberculosis; Whole genome sequencing", "medline_ta": "Braz J Infect Dis", "mesh_terms": "D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004351:Drug Resistance; D054908:Extensively Drug-Resistant Tuberculosis; D006801:Humans; D009169:Mycobacterium tuberculosis; D013997:Time Factors", "nlm_unique_id": "9812937", "other_id": null, "pages": "290-3", "pmc": null, "pmid": "27004922", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": null, "title": "Evaluation of resistance acquisition during 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{ "abstract": "BACKGROUND\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4% of all ectopic pregnancies. It also represents one of the few times an ectopic pregnancy can be carried to term. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk. After an extensive search of the English language medical literature, we are unaware of any case of abdominal pregnancy in which the placenta was receiving its vascular supply from the sacral plexus.\n\n\nMETHODS\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days' gestation, presented to our Emergency Department with abdominal pain. She did not complain of any vaginal bleeding. A physical examination revealed mild abdominal tenderness and no blood in the vaginal vault. Laboratory findings corresponded to an increased level of beta human chorionic gonadotropin; magnetic resonance imaging confirmed an abdominal pregnancy. She underwent feticide, administration of methotrexate and a laparotomy was done which was immediately deferred due to perceived increased bleeding risk. She was found to have an intra-abdominal ectopic pregnancy with the placenta attached to her omentum, cul-de-sac and rectosigmoid, with unusual and extensive vascularity from the sacral plexus. A repeat laparotomy was performed 11 weeks later, aimed at removal of the gestational sac and placenta that were left in situ on the first laparotomy. This time, we achieved successful removal of the peritoneal gestation, lysis of adhesions, ligation of vascular supply and cautery of the diminished vasculature. Subsequently, she had two ectopic pregnancies, which were managed with both medical and surgical interventions.\n\n\nCONCLUSIONS\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10% of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in future pregnancies. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility; however, surgery remains an acceptable modality. We found that careful and strategic choice of management pathway can make all the difference to a favorable outcome. As emergency physicians, we need to be aware of the possibility of abdominal ectopic pregnancy in such presentations and its severe consequences if it remains undiagnosed.", "affiliations": "Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. drpatelchaitali@gmail.com.;Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. jfeldman@hackensackUMC.org.;Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. cogedegbe@hackensackUMC.org.", "authors": "Patel\|Chaitali\|C\|;Feldman\|Joseph\|J\|;Ogedegbe\|Chinwe\|C\|", "chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate", "country": "England", "delete": false, "doi": "10.1186/s13256-016-0808-8", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 80810.1186/s13256-016-0808-8Case ReportComplicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4-year follow-up: a case report Patel Chaitali drpatelchaitali@gmail.com Feldman Joseph jfeldman@hackensackUMC.org Ogedegbe Chinwe cogedegbe@hackensackUMC.org Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ 07601 USA 11 2 2016 11 2 2016 2016 10 3725 9 2015 10 1 2016 © Patel et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4 % of all ectopic pregnancies. It also represents one of the few times an ectopic pregnancy can be carried to term. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk. After an extensive search of the English language medical literature, we are unaware of any case of abdominal pregnancy in which the placenta was receiving its vascular supply from the sacral plexus.\n\nCase presentation\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days’ gestation, presented to our Emergency Department with abdominal pain. She did not complain of any vaginal bleeding. A physical examination revealed mild abdominal tenderness and no blood in the vaginal vault. Laboratory findings corresponded to an increased level of beta human chorionic gonadotropin; magnetic resonance imaging confirmed an abdominal pregnancy. She underwent feticide, administration of methotrexate and a laparotomy was done which was immediately deferred due to perceived increased bleeding risk. She was found to have an intra-abdominal ectopic pregnancy with the placenta attached to her omentum, cul-de-sac and rectosigmoid, with unusual and extensive vascularity from the sacral plexus. A repeat laparotomy was performed 11 weeks later, aimed at removal of the gestational sac and placenta that were left in situ on the first laparotomy. This time, we achieved successful removal of the peritoneal gestation, lysis of adhesions, ligation of vascular supply and cautery of the diminished vasculature. Subsequently, she had two ectopic pregnancies, which were managed with both medical and surgical interventions.\n\nConclusions\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10 % of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in future pregnancies. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility; however, surgery remains an acceptable modality. We found that careful and strategic choice of management pathway can make all the difference to a favorable outcome.\n\nAs emergency physicians, we need to be aware of the possibility of abdominal ectopic pregnancy in such presentations and its severe consequences if it remains undiagnosed.\n\nKeywords\nAbdominal pregnancyEctopicLaparoscopyLaparotomyPeritonealPlacentaRecurrent ectopic pregnancySacral plexusSalpingotomyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nEctopic pregnancy occurs when the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. Abdominal pregnancies are rare types of ectopic pregnancies with high rates of maternal morbidity and mortality when encountered anywhere in the world [1]. Abdominal pregnancy accounts for up to 1.4 % of ectopic pregnancies [2]. The prevalence of ectopic pregnancy among women who go to an emergency department with first trimester bleeding, pain, or both ranges from 6 to 16 % [3]. These pregnancies can go undetected until an advanced fetal age and often result in severe hemorrhage [4]. Rates of maternal mortality for ectopic pregnancy in the United States have been reported as high as 20 % [5, 6]. The most common extrauterine location is the fallopian tube, accounting for 98 % of all ectopic gestations, but other possible sites include: cervical, interstitial (also referred to as cornual), hysterotomy scar, intramural, ovarian, or abdominal. Risk factors for ectopic pregnancy should be sought, including prior ectopic pregnancy, current use of an intrauterine device, prior tubal ligation, and in vitro fertilization (IVF). The risk of ectopic pregnancy increases with advancing maternal age, age over 35 years being a significant risk factor [1], and one third of the cases are thought to be associated with cigarette smoking [7]. The clinical presentation is variable, and the optimal approach to the evaluation and management of abdominal pregnancy is not well determined [8, 9]. Diagnosis can be made with a transvaginal ultrasound scan (TVS) which can identify an intrauterine pregnancy (IUP) or ectopic pregnancy [10]. In cases where an abdominal ectopic pregnancy is suspected and ultrasound is inconclusive, a diagnostic laparoscopy may be required [11]. Management of these pregnancies has changed dramatically over the years [12]. Medical and surgical interventions to these rare pregnancies are considered based on their presentation. Methotrexate treatment may be administered on a case-by-case basis, but surgical involvement may be imperative for some patients with abdominal pregnancies, particularly those presenting with rupture and who are in a state of hypovolemic shock and compromise. The 1997 to 1999 and 2003 to 2005 Confidential Enquiries into Maternal Deaths in the United Kingdom reports highlighted that most of the women who died from ectopic pregnancy were misdiagnosed in the primary care or accident and emergency settings [13, 14].\n\nWe present an unusual case that highlights the difficult clinical course of an abdominal ectopic pregnancy managed via strategic procedural intervention, as well as two separate presentations of recurrent ectopic pregnancies over a 4-year follow-up period in the same patient.\n\nCase presentation\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days’ gestation, presented to our ED with increasing abdominal pain and a positive home pregnancy test. She admitted that she had not been receiving prenatal care. She also asked for a termination of this pregnancy, if we confirmed that it was “abnormal”.\n\nShe described 3 out of 10 (mild) bilateral abdominal pain but denied any vaginal bleeding, nausea, vomiting, headache, fever, chills, dysuria or hematuria. She reported 1 to 2 weeks of severe constipation, but denied any melena or hematochezia. She also denied any history of abnormal pap smears, sexually transmitted diseases, or abnormal menses. At the time of her ED presentation she was not on any medications. She had a one pack week cigarette smoking history but denied any alcohol or other drug use. She reported being sexually active with one partner. She further mentioned that she was at a nearby hospital where pregnancy was confirmed and further testing had been done from where she signed out against medical advice (AMA).\n\nHer vital signs were: blood pressure (BP) 125/67 mmHg, pulse 115/minute, temperature 98.7 °F (37.1 °C), respiratory rate 16/minute, body mass index (BMI) 17.75 kg/m2, and oxygen saturation (SPO2) 99 %.\n\nHer physical examination was only significant for a soft non-distended abdomen, with mild diffuse lower abdominal tenderness maximal in the left lower quadrant of her abdomen. A pelvic examination, including a speculum examination, documented a normal appearing cervix, no active bleeding, and non-tender adnexa; a bimanual examination confirmed her cervix was closed and her uterus was enlarged, approximately 8 weeks in size. In our ED, she was seen by Obstetrics/Gynecology consult service. Diagnostics included initial and interval laboratory testing, as well as imaging studies, which included an ultrasound of the abdomen (transvaginal and transabdominal), magnetic resonance imaging (MRI) and a computed axial tomography (CAT) scan, (see Fig 1) of her abdomen. The results were as follows:Initial laboratory results were hemoglobin (Hb) 9.8 (anemia), hematocrit (HCT) 27.2, platelets 148, white blood cell count (WBC) 7.4, blood urea nitrogen (BUN) 4, creatinine 0.5, electrolytes were within normal ranges, albumin 2.9, partial thromboplastin time (PTT) 33, international normalized ratio (INR) 1.1, prothrombin time (PT) 13.5, beta human chorionic gonadotropin (BHCG) 134,494, fibrinogen 439, human immunodeficiency virus (HIV)-negative and RH positive.\n\nMRI: intra-abdominal ectopic pregnancy with the placenta connected to the sacral plexus. Ultrasound of the abdomen (transvaginal and transabdominal), (see Fig 2) as well as abdominal CAT scans with and without contrast showed uterus measuring 9.0×5.8×8.2 cm; no IUP; live intra-abdominal pregnancy was present within her pelvis, ventral to the uterus and measuring 7.2×12 cm.Fig. 1 Computed tomography angiogram of abdomen and pelvis. 1 Intra-abdominal pregnancy. 2 Hematoma in cul-de-sac. 3 Uterus\n\nFig. 2 Ultrasound of abdomen and pelvis. 1 Gestational sac. 2 Fetus (extrauterine pregnancy – right adnexa)\n\n\n\n\n\nShe was counselled on termination of the pregnancy due to the gravity of the medical and surgical comorbidities, and she underwent feticide via ultrasound-guided fetal intracardiac potassium chloride injection on the second day after presentation, gestational age corresponding to 16 weeks and 6 days. She received four alternate doses of methotrexate on the third, fifth and seventh day from presentation with interval leucovorin rescue on alternate days and then had an infraumbilical laparotomy for pelvic exploration and planned fetus removal. A laparotomy was initiated and during the procedure it was found that there was extensive vascularity and attachment of the gestational sac to her omentum, mesentery, loops of bowel, lateral pelvic wall, and predominantly her uterine wall. The vascularity was mainly derived from the sacral plexus and the left external iliac artery, and the patient was deemed inoperable due to the high risk of hemorrhage, need for bowel resection, and potential hysterectomy. Consequently, no attempt was made to remove the gestational sac, the placenta was left in situ as well, and the planned fetus removal was deferred to a later date. She was discharged to follow-up at clinic for serial monitoring of her BHCG levels every week, and expectant management. She returned to our ED 11 weeks after feticide with complaints of abdominal pain and vaginal bleeding. A strategic decision was made to bring her to the Operating Room (OR) 2 days later for a second laparotomy, this time with lysis of adhesions, removal of abdominal pregnancy and left salpingo-oophorectomy, which was thought to be the primary site of implantation prior to secondary implantation in her peritoneum. She tolerated the intervention and no adverse or unanticipated event was noted. She was discharged and asked to follow-up with BHCG levels until her levels returned to normal and to return for any further complaints. She adhered to the advice and was counselled not to get pregnant for a year.\n\nTwo years later, she presented to our ED with abdominal pain and nausea. Diagnosis was made of a second ectopic pregnancy in her right fallopian tube, with gestational age corresponding to 6 weeks. She received expectant medical management with methotrexate administration: first dose on the day of presentation, second and third doses, 4 and 7 days after the first methotrexate dose was given. Her BHCG levels were monitored and were seen to trend down from 7026 mIU/ml to 5368 and 3739 and complete resolution of this second ectopic pregnancy was noted. She presented with abdominal pain at our ED approximately 8 months after her second ectopic pregnancy. A TVS confirmed a third ectopic pregnancy, at 5 weeks and 5 days of gestation, adjacent to her right ovary. An exploratory laparotomy was performed with right salpingotomy and ectopic removal after she consented to surgery.\n\nDiscussion\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4 % of all ectopic pregnancies [15]; “it also represents one of the few times an ectopic pregnancy can be carried to term” [16]. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk.\n\nTo the best of our knowledge, our case report represents the first report of an abdominal ectopic pregnancy with a blood supply from the sacral plexus. The consistent clinical presentation of our patient was abdominal pain and nausea, whereas the most common clinical presentation of ectopic pregnancy is early trimester vaginal bleeding and/or abdominal pain [17]. Currently, diagnosis in unruptured ectopic pregnancy is achieved using a combination of transvaginal ultrasonography and measurement of serum BHCG concentrations [11]. Diagnosis can be straightforward when a TVS positively identifies an IUP or ectopic pregnancy [10]. In cases where an ectopic pregnancy is suspected and ultrasound is inconclusive, a diagnostic laparoscopy may be required; this is believed by many to be the ‘gold standard’ investigation in ectopic pregnancy [10]. The patient in our case had all the diagnostic tests, including a laparotomy for the removal of the fetus and the gestational sac during the initial ectopic (abdominal) pregnancy, when she presented with severe abdominal pain. Consequent to the earlier methotrexate administration, repeat abdominal examinations and expectant management, it was thought that the gestational sac, fetus and placenta would continue to be reabsorbed and diminish in volume and complexity, as found at the second laparotomy. The placenta was more easily separated from the sacral plexus and internal iliac vessels with standard surgical procedures, including vascular supply ligation and cautery. “Treatment with pre-operative systemic methotrexate with subsequent laparotomy for removal of the fetus and placenta may minimize potential blood loss, and would be a reasonable approach in the care of a patient with an abdominal pregnancy with placental implantation to the abdominal viscera and blood vessels” [18], as noted here in a 16-week gestation case. During surgery, if the placenta is attached to vital organs it should be left behind [18]. Eleven weeks after the feticide procedure and previous laparotomy, we expected the sac to be completely reabsorbed and eventually not to perform any more invasive procedures. We were surprised at the finding that the products of conception (POC) were not completely reabsorbed and the POC was still at the size of 17 weeks, although it was 11 weeks post-feticide procedure. Reluctance or delay in performing a diagnostic laparoscopy has been highlighted as a factor in fatal cases [19]. The second laparotomy was successful, and on observation of the tubes and uterus, a rupture site was noted on the left tube, which was the reason for the left salpingo-oophorectomy. Post-surgery our patient did well with Hb within normal limits, and no further complaints or complications were noted. A laparotomy should be reserved for patients who present with rupture and are in a state of hypovolemic shock and compromise [11]; however, our patient was deemed unfit for definitive management by laparoscopy because of the extensive vascularity of her placenta from the surrounding structures, and therefore had a laparotomy.\n\nIf BHCG concentrations are falling but an ectopic pregnancy has not been excluded, then consideration should be given to performing serial BHCG measurements until levels become undetectable, as rupture can still occur [20]. Laparoscopic procedures are associated with shorter operative times, less intraoperative blood loss, shorter hospital stays and lower analgesia requirements [21–23], compared to laparotomy.\n\nThe conclusions and recommendations in the “Practice Bulletin, June 2008, Medical Management of Ectopic Pregnancy” of the American Congress of Obstetricians and Gynecologists (ACOG) state that the results of randomized trials in which systemic methotrexate with tube-sparing laparoscopic surgery were compared showed no difference in overall tubal preservation, tubal patency, repeat ectopic pregnancy, or future pregnancies, based on good and consistent evidence. In contrast to tubal ectopic pregnancies, primary methotrexate therapy for early gestation in abdominal pregnancies has had minimal success [24]. This was different to our case, where the second ectopic (6 weeks) was reabsorbed and our patient’s BHCG levels returned to normal after methotrexate treatment. It further suggests that failure of the BHCG level to decrease by at least 15 % from day 4 to day 7 after methotrexate administration is considered treatment failure requiring therapy with either additional methotrexate administration or surgical intervention.\n\nIn our patient, even though her BHCG levels were trending down by 15 % and more with each passing day, a surgical intervention was unavoidable due to the unusual location and unabsorbed gestational sac. The Practice Committee of the American Society for Reproductive Medicine suggested that ovarian and abdominal pregnancies should be diagnosed definitively at the time of surgical exploration, and both conservative surgery and medical therapy may be viewed as appropriate first-line therapies in many early unruptured ectopic pregnancies [25]. As elected in our case, surgical intervention was the initial step in the management of our patient’s ectopic pregnancy.\n\nThe strength of our case report was the strategic approach to management, which included a stepwise combination therapy approach, tailored to the patient’s clinical condition, with some input from her and shared decision making with her.\n\nThere is a 5 to 20 % risk of a recurrence of ectopic pregnancy with one previous ectopic pregnancy and a risk of 32 % or more following more than one previous ectopic pregnancy [11]. The second ectopic pregnancy in our patient was uneventful with medical management and reabsorption of the POC. With regards to her third ectopic pregnancy, she initially refused any interventions and only accepted methotrexate administration on the day of presentation at 5 weeks and 5 days of gestational age, the second dose on day 3 and the third dose on day 7, after her initial dose, with follow-up of BHCG levels every 3 days. However, she returned 10 days later, with right lower quadrant (RLQ) pain and gestational age corresponding to 7 weeks; laparotomy with planned salpingotomy was identified as the best choice after a shared decision-making process. Our patient, an educated African-American woman had access to our hospital and emergency care, was also employed, but without medical insurance. While talking about her experience, she mentioned her financial constraints and the lack of a proper insurance policy, which had impacted her life and her earlier decisions of signing out AMA. Involving social services and encouraging shared decision making with the patient, regarding her procedure choices, her health and her future reproductive life, were critical in the successful outcome of this case.\n\nConclusions\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location, such as the cervix, ovary, abdomen, liver, spleen or caesarean section scar [26]. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10 % of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in subsequent pregnancies [27]. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility [28]. Surgery remains an acceptable, and sometimes necessary, modality for the treatment of ectopic pregnancy [29]. Counselling in these patients, as well as shared decision making, represents an important aspect, as they require a lot of care and understanding of the future risks of similar pregnancies. A careful and strategic choice of management pathway can make all the difference to a favorable outcome.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nAMAAgainst medical advice\n\nBHCGBeta human chorionic gonadotropin\n\nCATComputed axial tomography\n\nEDEmergency Department\n\nHbHemoglobin\n\nIUPIntrauterine pregnancy\n\nMRIMagnetic resonance imaging\n\nPOCProducts of conception\n\nTVSTransvaginal ultrasound scan\n\nCompeting interests\n\nThe authors declare that they have no competing interests. We wish to confirm that there are no known conflicts of interest associated with this publication.\n\nAuthors’ contributions\n\nCP did the search and review of the current medical literature for this manuscript; CP also wrote the initial draft of the manuscript for this case report, guided and supervised by CO. JF reviewed the entire manuscript, suggested changes and edited the manuscript. CO had the concept of the manuscript write up after the case presented to our ED. CO reviewed, edited and proofed the entire case report. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship who are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.\n\nAuthors’ information\n\nChaitali Patel, MD – Emergency Medicine Research Associate, Hackensack University Medical Center.\n\nJoseph Feldman, MD – Chairman of Emergency Medicine, Hackensack University Medical Center.\n\nChinwe Ogedegbe, MD, MPH – Attending Physician and Director of Research Emergency Medicine, Hackensack University Medical Center.\n\nAlthough Dr Patel will remain first author, Dr Ogedegbe will serve as the corresponding author.\n\nAll reviewers work at: Hackensack University Medical Center, 30, Prospect Ave, Hackensack, New Jersey, 07601, USA.\n\nAcknowledgements\nWe wish to confirm that here has been no significant financial support for this work that could have influenced its outcome.\n==== Refs\nReferences\n1. Farquhar CM Ectopic pregnancy Lancet 2005 366 9485 583 91 10.1016/S0140-6736(05)67103-6 16099295 \n2. Dover RW Powell MC Management of a primary abdominal pregnancy Am J Obstet Gynecol 1995 172 5 1603 4 10.1016/0002-9378(95)90504-9 7755078 \n3. Murray H Baakdah H Bardell T Tulandi T Diagnosis and treatment of ectopic pregnancy CMAJ 2005 173 8 905 12 10.1503/cmaj.050222 16217116 \n4. Fisch B Peled Y Kaplan B Zehavi S Neri A Abdominal pregnancy following in vitro fertilization in a patient with previous bilateral salpingectomy Obstet Gynecol 1996 88 4 Pt 2 642 3 10.1016/0029-7844(96)00213-X 8841236 \n5. Onan MA Turp AB Saltik A Akyurek N Taskiran C Himmetoglu O Primary omental pregnancy: case report Hum Reprod 2005 20 3 807 9 10.1093/humrep/deh683 15640259 \n6. Varma R Mascarenhas L James D Successful outcome of advanced abdominal pregnancy with exclusive omental insertion Ultrasound Obstet Gynecol 2003 21 2 192 4 10.1002/uog.25 12601846 \n7. Bouyer J Coste J Shojaei T Pouly JL Fernandez H Gerbaud L Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France Am J Epidemiol 2003 157 3 185 94 10.1093/aje/kwf190 12543617 \n8. Nkusu Nunyalulendho D Einterz EM Advanced abdominal pregnancy: case report and review of 163 cases reported since 1946 Rural Remote Health 2008 8 4 1087 19053177 \n9. Molinaro TA, Barnhart KT. Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy; UpToDate: http://www.uptodate.com/contents/abdominal-pregnancy-cesarean-scar-pregnancy-and-heterotopic-pregnancy\n10. Condous G Timmerman D Goldstein S Valentin L Jurkovic D Bourne T Pregnancies of unknown location: consensus statement Ultrasound Obstet Gynecol 2006 28 2 121 2 10.1002/uog.2838 16933302 \n11. Sivalingam VN Duncan WC Kirk E Shephard LA Horne AW Diagnosis and management of ectopic pregnancy J Fam Plann Reprod Health Care 2011 37 4 231 40 10.1136/jfprhc-2011-0073 21727242 \n12. Yao M Tulandi T Current status of surgical and nonsurgical management of ectopic pregnancy Fertil Steril 1997 67 3 421 33 10.1016/S0015-0282(97)80064-7 9091325 \n13. Lewis G The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving mothers’ lives: reviewing maternal deaths to make motherhood safe 2003-2005. RCOG Press; London, UK: 2007 Semin Perinatol 2012 36 1 22 6 10.1053/j.semperi.2011.09.005 \n14. O'Herlihy C Deaths in early pregnancy; Centre for Maternal and Child Enquiries (CMACE). Saving mothers’ lives: reviewing maternal deaths to make motherhood safe 2006-2008 2011 London RCOG Press 81 4 \n15. Karaer O Ilkgül O Oruç S Primary omental pregnancy on the gastrocolic ligament South Med J 2007 100 4 403 4 10.1097/01.smj.0000254211.50103.e6 17458402 \n16. Ludwig M Kaisi M Bauer O Diedrich K Case report: the forgotten child – a case of heterotopic, intra-abdominal and intrauterine pregnancy carried to term Hum Reprod 1999 14 5 1372 4 10.1093/humrep/14.5.1372 10325296 \n17. Alkatout I Honemeyer U Strauss A Tinelli A Malvasi A Jonat W Clinical diagnosis and treatment of ectopic pregnancy Obstet Gynecol Surv 2013 68 8 571 81 10.1097/OGX.0b013e31829cdbeb 23921671 \n18. Gupta P Sehgal A Huria A Mehra R Secondary abdominal pregnancy and its associated diagnostic and operative dilemma – three case reports J Med Case Reports. 2009 3 7382 10.4076/1752-1947-3-7382 \n19. Robson SJ O’Shea RT Undiagnosed ectopic pregnancy: a retrospective analysis of 31 ‘missed’ ectopic pregnancies at a teaching hospital Aust N Z J Obstet Gynaecol 1996 36 2 182 5 10.1111/j.1479-828X.1996.tb03282.x 8798311 \n20. Morin L Van den Hof MC Ultrasound evaluation of first trimester pregnancy complications; Diagnostic Imaging Committee, Society of Obstetricians and Gynaecologists of Canada J Obstet Gynaecol Can. 2005 27 581 91 16100636 \n21. Parker J Bisits A Laparoscopic surgical treatment of ectopic pregnancy: salpingectomy or salpingostomy? Aust N Z J Obstet Gynaecol. 1997 37 115 7 10.1111/j.1479-828X.1997.tb02232.x 9075562 \n22. Clausen I Conservative versus radical surgery for tubal pregnancy. A review Acta Obstet Gynecol Scand 1996 75 1 8 12 10.3109/00016349609033276 8561006 \n23. Thornton KL Diamond MP DeCherney AH Linear salpingostomy for ectopic pregnancy Obstet Gynecol Clin North Am. 1991 18 95 109 1923258 \n24. Zinger M Rosenfeld D Failed treatment of abdominal pregnancy with methotrexate. A case report J Reprod Med 2001 46 4 392 4 11354843 \n25. Correspondence: A Practice Committee, American Society for Reproductive Medicine, Birmingham, Alabama; Fertility and Sterility® Vol. 100, No. 3, September 2013 0015-0282; https://www.asrm.org/uploadedFiles/ASRM_Content/News_and_Publications/Practice_Guidelines/Committee_Opinions/optimizing_natural_fertility(1).pdf\n26. Walker JJ Ectopic pregnancy Clin Obstet Gynecol. 2007 50 89 99 10.1097/GRF.0b013e31802f4f79 17304026 \n27. Marion LL Meeks GR Ectopic pregnancy: history, incidence, epidemiology, and risk factors Clin Obstet Gynecol 2012 55 2 376 86 10.1097/GRF.0b013e3182516d7b 22510618 \n28. Juneau C Bates GW Reproductive outcomes after medical and surgical management of ectopic pregnancy Clin Obstet Gynecol 2012 55 2 455 60 10.1097/GRF.0b013e3182510a88 22510628 \n29. Stock L Milad M Surgical management of ectopic pregnancy Clin Obstet Gynecol 2012 55 2 448 54 10.1097/GRF.0b013e3182510a19 22510627\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "10()", "journal": "Journal of medical case reports", "keywords": null, "medline_ta": "J Med Case Rep", "mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008160:Lumbosacral Plexus; D008727:Methotrexate; D010920:Placenta; D011247:Pregnancy; D011269:Pregnancy, Abdominal; D012008:Recurrence", "nlm_unique_id": "101293382", "other_id": null, "pages": "37", "pmc": null, "pmid": "26868918", "pubdate": "2016-02-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12601846;7755078;15640259;8841236;21727242;9091325;8561006;16099295;9075562;19830195;11354843;12543617;19053177;16100636;22510628;10325296;16217116;8798311;22510627;1923258;17304026;17458402;23921671;22510618;16933302", "title": "Complicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4-year follow-up: a case report.", "title_normalized": "complicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4 year follow up a case report" }	[ { "companynumb": "US-ANTARES PHARMA, INC.-2016-LIT-ME-0254", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "204824", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ABORTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATEL, ET.AL... 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{ "abstract": "While cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is the most commonly used chemotherapeutic regimen for patients with peripheral T-cell lymphomas (PTCLs), elderly patients are more vulnerable to associated toxicities. We evaluated the efficacy and safety of dose-attenuated CHOP in elderly patients with PTCL.\nPatients with PTCL aged >70 years or 65-70-years with comorbidities were treated with dose-attenuated CHOP (cyclophosphamide: 562.5 mg/m2, doxorubicin: 37.5 mg/m2, vincristine: 1.4 mg/m2, and prednisolone: 100 mg for five days; 25% reduced dose of cyclophosphamide and doxorubicin vs. full-dose CHOP) as first-line therapy were included.\nForty-four patients (median age, 74 yr) were analyzed. The majority (N=42, 95.5%) had advanced stage disease and 36 (81.8%) were classified as high/high-intermediate risk by the international prognostic index. The overall response rate was 61.4%, and 21 patients achieved complete response (47.7%). With median follow-up period of 28.8 months, the estimated two-year progression-free and overall survival rates were 36.7% and 46.6%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 26.9% and 7.4% of 204 total cycles, which affected 76.7% and 25.6% of the patients, respectively. Nineteen patients (44.2%) experienced febrile neutropenia, and six died due to treatment-related toxicities. High lactate dehydrogenase levels and an involvement of >1 extranodal sites were prognostic indicators of poor survival.\nDose-attenuated CHOP does not compromise treatment efficacy but retains significant toxicity. Our results suggest that some patients can be effectively treated with dose-attenuated CHOP, however a novel therapy for elderly patients with PTCL is required.", "affiliations": "Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.", "authors": "Choi\|Eun-Ji\|EJ\|;Hong\|Jung Yong\|JY\|;Yoon\|Dok Hyun\|DH\|;Kang\|Jihoon\|J\|;Park\|Chan-Sik\|CS\|;Huh\|Jooryung\|J\|;Chae\|Eun Jin\|EJ\|;Lee\|Yoonse\|Y\|;Ryu\|Jin-Sook\|JS\|;Suh\|Cheolwon\|C\|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5045/br.2017.52.4.270", "fulltext": "\n==== Front\nBlood ResBlood ResBRBlood research2287-979X2288-0011Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 10.5045/br.2017.52.4.270Original ArticleTreatment outcomes of dose-attenuated CHOP chemotherapy in elderly patients with peripheral T cell lymphoma Choi Eun-Ji 1Hong Jung Yong 2Yoon Dok Hyun 2Kang Jihoon 2Park Chan-Sik 3Huh Jooryung 3Chae Eun Jin 4Lee Yoonse 5Ryu Jin-Sook 6Suh Cheolwon 21 Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.4 Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.5 Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.6 Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.\nCorrespondence to Cheolwon Suh, M.D., Ph.D. Department of Oncology, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. csuh@amc.seoul.kr\nCorrespondence to Dok Hyun Yoon, M.D., Ph.D. Department of Oncology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. dhyoon@amc.seoul.kr12 2017 26 12 2017 52 4 270 275 25 4 2017 13 5 2017 25 6 2017 © 2017 Korean Society of Hematology2017Korean Society of HematologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nWhile cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is the most commonly used chemotherapeutic regimen for patients with peripheral T-cell lymphomas (PTCLs), elderly patients are more vulnerable to associated toxicities. We evaluated the efficacy and safety of dose-attenuated CHOP in elderly patients with PTCL.\n\nMethods\nPatients with PTCL aged >70 years or 65–70-years with comorbidities were treated with dose-attenuated CHOP (cyclophosphamide: 562.5 mg/m2, doxorubicin: 37.5 mg/m2, vincristine: 1.4 mg/m2, and prednisolone: 100 mg for five days; 25% reduced dose of cyclophosphamide and doxorubicin vs. full-dose CHOP) as first-line therapy were included.\n\nResults\nForty-four patients (median age, 74 yr) were analyzed. The majority (N=42, 95.5%) had advanced stage disease and 36 (81.8%) were classified as high/high-intermediate risk by the international prognostic index. The overall response rate was 61.4%, and 21 patients achieved complete response (47.7%). With median follow-up period of 28.8 months, the estimated two-year progression-free and overall survival rates were 36.7% and 46.6%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 26.9% and 7.4% of 204 total cycles, which affected 76.7% and 25.6% of the patients, respectively. Nineteen patients (44.2%) experienced febrile neutropenia, and six died due to treatment-related toxicities. High lactate dehydrogenase levels and an involvement of >1 extranodal sites were prognostic indicators of poor survival.\n\nConclusion\nDose-attenuated CHOP does not compromise treatment efficacy but retains significant toxicity. Our results suggest that some patients can be effectively treated with dose-attenuated CHOP, however a novel therapy for elderly patients with PTCL is required.\n\nPeripheral T cell lymphomaElderlyDose-attenuated CHOP\n==== Body\nINTRODUCTION\nPeripheral T cell lymphoma (PTCL) represents a group of heterogeneous lymphoproliferative disorders arising from the clonal expansion of post-thymic T cells or natural killer (NK) cells [1]. While PTCL is a relatively uncommon disease, which accounts for <20% of all non-Hodgkin lymphoma (NHL) cases, the prevalence of PTCL in Asian countries is higher than in the West [23]. The clinical course of PTCLs is typically aggressive and associated with poor prognosis with five-year overall survival (OS) rates below 30% [3456].\n\nThe median age for PTCL development was reported to be 62 years in the international T-cell lymphoma projects, and according to SEER data, approximately 40% of patients with PTCL are above the age of 70 years [37]. Moreover, elderly patients have a poor tolerance to chemotherapy due to impaired bone marrow (BM) function, altered drug metabolism, and presence of comorbid diseases. Thus, elderly patient with PTCL often suffer from increased susceptibility to treatment-related complications [68].\n\nAlthough there is no consensus based on randomized trials regarding an optimal first-line chemotherapy for PTCLs, anthracycline-based CHOP-like regimens have been the most common treatment. However, optimal dosing for elderly patients has not been specifically addressed. In this study, we attempted to reduce the dose of two myelotoxic agents (cyclophosphamide and doxorubicin) by 25% from the full-dose CHOP regimen, with the aim of decreasing chemotherapy-related hematologic and/or infectious complications in elderly patients. We assessed the efficacy and safety of a dose-attenuated CHOP regimens in patients with PTCL aged over 70 years and those aged between 65–70-year with comorbidities that were either expected to result in significant treatment-related toxicities or included in the parameters of a comprehensive geriatric assessment.\n\nMATERIALS AND METHODS\nPatient population\nThe data of 44 consecutive elderly patients with PTCL were used for analysis in this study. We included patients aged between 65 and 70 years, with comorbidities that were expected to result in significant treatment-related toxicities or included in the parameters of a comprehensive geriatric assessment [such as heart failure (NYHA III-IV), coronary artery disease, cardiac arrhythmia, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, renal insufficiency (creatinine clearance ≤50 mL/min), cirrhosis, post-stroke neurologic sequelae, and/or medically unfit condition] [910], and patients aged over 70 years who were treated with dose-attenuated CHOP chemotherapy between April 2001 and 2015. All patients underwent pre-treatment heart scan or transthoracic echocardiography, and those with significant cardiac dysfunction were excluded due to risk of anthracycline cardiotoxicity. Diagnosis of PTCL was confirmed by a certified hematopathologist, according to World Health Organization (WHO) criteria [11]. We excluded patients with extranodal NK/T cell lymphoma, nasal-type (ENKTL) or adult T cell leukemia/lymphoma, and those who had previously received other chemotherapeutic agents for lymphoma. The study protocol was approved by the Institutional Review Board (2016-0568) in accordance with the 2008 Declaration of Helsinki.\n\nDisease evaluation\nAll patients were staged according to the Lugano classification at the time of diagnosis based on results of their medical history, physical examination, complete blood count, serum lactate dehydrogenase (LDH), computed tomography (CT), BM aspiration and biopsy, and a positron emission tomography-CT (PET-CT) scan [12]. Response to treatment was assessed after four and six cycles of dose-attenuated CHOP chemotherapy or whenever progressive disease was suspected based on international criteria [13]. Hematologic and major treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.\n\nTreatment\nThe dose-attenuated CHOP regimen consisted of 562.5 mg/m2 cyclophosphamide administered intravenously for one day (25% reduction from full-dose CHOP), 37.5 mg/m2 doxorubicin for one day (25% reduction from full-dose CHOP), 1.4 mg/m2 vincristine for one day, and 50 mg prednisolone twice a day for five days. Patients were scheduled to receive six cycles of dose-attenuated CHOP at three-week intervals, however the treatment interval could be modified at the physician's discretion after considering blood count recovery or the patients' general condition. Primary prophylactic pegylated granulocyte-colony stimulating factor (peg-G-CSF) was routinely administered to nine patients treated since August 2014, when peg-G-CSF was reimbursed by national health insurance. In the event of severe neutropenia or febrile neutropenic events, G-CSF was administered subcutaneously to patients who were not given prophylactic peg-G-CSF. The dose of cyclophosphamide and doxorubicin was reduced by an additional 25% if the ANC and platelet counts did not recover to less than grade 1, even after a two-week delay, or according to physician discretion.\n\nStatistical analysis\nOverall survival (OS) was calculated from the date of the diagnosis to the date of last follow-up or death due to any cause. Progression-free survival (PFS) was defined as the duration from the date of diagnosis to the date of progression, relapse, or death from any cause. Efficacy analyses were performed using the intention-to-treat principle. Survival was calculated using the Kaplan–Meier method and analyzed using a log-rank test for univariate analysis and a Cox regression model for multivariate analysis. Variables with P<0.1 in the univariate analysis were selected for the multivariate analysis models. Two-sided P<0.05 was considered statistically significant.\n\nRESULTS\nPatient characteristics\nCharacteristics of the 44 elderly patients with PTCL are summarized in Table 1. The diagnoses included PTCL-not otherwise specified (NOS) (N=27), angioimmunoblastic T cell lymphoma (N=9), anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (N=5), and enteropathy-associated T cell lymphoma (N=3). The median age at diagnosis was 74 years (range, 65–86 yr). Of the 15 patients aged between 65 and 70 years, there were three with diabetes mellitus and hypertension, one with diabetes mellitus and angina, three who had an immobilized status associated with a compression fracture, one with arrhythmia (atrial fibrillation), one with liver cirrhosis, one with post-stroke neurologic sequelae, one with myelodysplastic syndrome, one with major depression, one with chronic lung disease, one with poor nutritional status with post-op leakage after small bowel resection, and one with panhypopituitarism. Three patients were identified as positive for hepatitis B surface antigen before treatment, two of whom were already on treatment with entecavir and the other one was given prophylactic tenofovir with chemotherapy. Most patients displayed an advanced disease stage (95.5%), and 36 (81.8%) patients were categorized as high-intermediate or high risk according to the International Prognostic Index (IPI) scoring system [14]. According to the Prognostic Index for PTCL-U (PIT), which includes age, Eastern Cooperative Oncology Group performance status (ECOG PS), LDH level, and BM involvement, 79.5% of the patients were classified into a high-risk group (PIT score>2) [4].\n\nResponse to treatment\nOf the 44 patients in the intention-to-treat population, 23 (52.3%) patients completed the six scheduled cycles of treatment. The causes of discontinuation included chemo-refractory or progressive disease within three cycles (N=11), infection (N=6), subdural hemorrhage (N=1), and intolerance (N=2), and one patient was lost to follow-up. Relative dose intensity for the 23 patients who completed treatment was 72.4±13.7% for both doxorubicin and cyclophosphamide. The response to treatment was assessable in 35 patients both during and at the end of treatment, however nine patients died or were lost to follow-up before the post-treatment evaluation. A total of 21 patients achieved complete response (CR) and six achieved partial response (PR); thus, the overall response rate (ORR) and CR rate were 61.4% and 47.7%, respectively. Of the 21 complete responders, 11 remained in remission for a median duration of 14.3 months (range, 1.4–158.1 mo), however 9 of the 21 complete responders and four of the six partial responders experienced disease relapse or progression after completing treatment. Of the other two patients who achieved PR, one died of pneumonia with septic shock 12 days after achieving PR, following three cycles of the chemotherapy, and the other was lost to follow-up four months after completion of six chemotherapy cycles.\n\nSurvival\nDuring the median follow-up duration for survivors (28.8 mo, range, 7.1–174.6 mo), 23 patients experienced disease progression and 23 patients died. The estimated two-year PFS and OS rates were 36.7% (95% CI: 27.9–45.5%) and 46.6% (95% CI: 37.7–53.3%), and the median PFS and OS were 8.2 and 11.7 months, respectively (Fig. 1). Of the 23 deaths, 16 were secondary to lymphoma progression, six were related to treatment toxicities (five infections and one bleeding), and one was due to an unknown cause.\n\nOf the 27 responders, 20 remained alive at the time of the analysis, whereas only one of eight non-responders survived. The surviving patient who did not respond to dose-attenuated CHOP received four cycles of gemcitabine-based cytotoxic chemotherapy (gemcitabine, dexamethasone, and cisplatin) as salvage treatment, achieved CR, and remained alive at the time of the analysis without evidence of disease. Thirteen patients survived for more than 48 months at the time of analysis, and these long-term survivors showed tendencies toward better performance status (ECOG PS 2–4 of 7.7% vs. 30.2%, P=0.1), less advanced stage (Ann Arbor stage III-IV of 76.9% vs. 100%, P=0.001), and less extranodal disease (>1 extranodal sites of 38.5% vs. 62.8%, P=0.120) than short-term survivors at baseline. In addition, long-term survivors had higher CR rates (92.3% vs. 39.5%, P=0.004) and experienced less grade 3 or 4 thrombocytopenia (0% vs. 35%, P=0.013) and neutropenia (61.5% vs. 82.5%, P=0.117). In the univariate analysis, ECOG PS >1 (P=0.023), high IPI score (P=0.043), and high PIT score (P=0.028) were associated with inferior PFS (Table 2). Patients with ECOG PS >1 (P=0.019), high LDH level (P=0.013), or disease involvement of >1 extranodal sites (P=0.003) had a shorter OS duration (Table 2). The Cox-regression model analysis revealed that poor ECOG PS [hazard ratio (HR): 5.14; 95% CI: 1.52–17.45; P=0.009] remained an independent prognostic factor for shorter PFS. The involvement of more than one extranodal site (HR: 4.78; 95% CI: 1.76–12.98; P=0.002) and a high LDH level (HR: 2.91; 95% CI: 1.08–7.87; P=0.035) were independent prognostic factors of inferior OS (Table 3).\n\nTreatment toxicity\nHematologic toxicities were evaluable in 43 of the 44 patients; one patient was lost to follow-up after the first cycle of chemotherapy. Grade 3 or 4 neutropenia was observed after 55 (26.9%) of the 204 total administered cycles, which affected 33 (76.7%) of 43 patients. Of these 55 neutropenic events, 42 (76.4%) occurred within the second cycle of chemotherapy. A total of 19 (44.2%) patients experienced febrile neutropenia during treatment, and three died of infectious complications. Grade 3 or 4 thrombocytopenia occurred after 15 (7.4%) out of 204 total cycles, which affected 11 (25.6%) of 43 patients. Although the difference was not significant, patients with BM involvement at the time of diagnosis experienced more severe neutropenia after chemotherapy, which was denoted by nadir ANC median counts of 345/µL with BM involvement, and 601/µL without BM involvement (P=0.074). Further dose reduction was necessary for 16 of 44 patients (36.4%) due to severe neutropenia that resulted in febrile neutropenic episodes. Among the nine patients who received primary prophylactic peg-G-CSF, seven (77.8%) and three (33.3%) patients experienced grade 3 or 4 neutropenia and febrile neutropenia, respectively. Of the 35 patients who did not receive prophylactic peg-G-CSF, 28 (80.0%) and 16 (45.7%) experienced grade 3 or 4 neutropenia and febrile neutropenia, respectively (P=0.754 for grade 3 or 4 neutropenia; P=0.461 for febrile neutropenia).\n\nThe most common non-hematologic serious adverse events were infections, and five patients (11.4%) experienced grade 3 or 4 infectious complications. Among these five patients, four died from septic shock within 28 days after the first cycle of chemotherapy. Five patients (11.4%) experienced grade 2 or higher sensory neuropathy during treatment, and one suffered from persistent cytopenia and a subdural hemorrhage, six weeks after the second cycle.\n\nDISCUSSION\nIn our study, we evaluated the outcomes of dose-attenuated CHOP chemotherapy for elderly PTCLs, which resulted in an ORR of 61.4%, CR rate of 47.7%, two-year PFS rate of 36.7%, and OS of 46.6%. These results appear comparable to those of previous studies involving full-dose CHOP chemotherapy that covered a 21-day interval. In the NHL-B2 trial of the DSHNHL, patient with B- and T-cell NHL aged between 61 and 75 years exhibited a CR rate of 60.1%, three-year event-free survival of 41.3%, and three-year OS of 48.8% [15]. In the GOELAMs-LTP95 prospective randomized study of PTCL, which compared VIP-reinforced ABVD with CHOP-21, 69% of patients were aged over 60 years, and the CR and two-year PFS rates in the CHOP group were 35% and 41%, respectively [16]. Recent multicenter data from South East Korea assessing the efficacy of various regimens, such as CHOP, CHOEP, IMEP, and CVP, in elderly patients with PTCL also reported an ORR of 70.2% with a CR rate of 37.8%, and the estimated five-year PFS and OS rates were 16.6% and 45.9%, respectively, which are similar to our results [17].\n\nIn the present study, a dose reduction of doxorubicin and cyclophosphamide failed to mitigate the toxicities associated with CHOP chemotherapy in elderly patients. The reduced treatment dose was still associated with elevated rates of hematologic toxicities, including grade 3 or 4 neutropenia and febrile neutropenic events in 76.7% and 44.2% of patients, respectively. This high rate of neutropenia was similar to the rate of 72.1% exhibited in the three-weekly CHOP arm of the NHL-B2 trial of DSHNHL [15]. In the GOELAMS-LTP95 trial, grade 3/4 neutropenia and thrombocytopenia episodes were observed in 8.3% and 1.6% of all cycles, respectively, with treatment-related deaths occurring in 6.7% of patients [16]. These might be attributed to reduced hematopoietic reserve, decreased hepatic and renal function associated with drug metabolism and excretion, changes in physiological body composition related to increased toxicity, and emotional frailty of elderly patients [18]. In the present study, 19 (43.2%) of the 44 patients had lymphoma with BM involvement at the time of diagnosis, and this incidence was much higher than the 3% to 29% rates of common PTCL subtypes obtained from an international PTCL study [3]. A Chinese study involving 56 patients with PTCL patients who were over 60 years in age also reported a substantially smaller proportion of BM involvement, at 7.0% [19]. Our results suggest that this high rate of BM involvement at least partially explains the higher frequencies of grade 3 or 4 neutropenia and febrile neutropenia events observed in our study. Old age is generally considered a risk factor for higher rates of neutropenic infections following CHOP treatment or CHOP-like regimens [2021], and several controlled trials and meta-analyses have revealed that the prophylactic use of peg-G-CSF reduces the occurrence of febrile neutropenic events [2223]. Although the present study included nine patients who received primary prophylactic peg-G-CSF, no significant differences in grade 3 or 4 neutropenia and febrile neutropenia were noted during the routine administration of prophylactic G-CSF, which could be attributed to the small number of patients in our study. In addition, six patients died of therapy-related toxicities without disease progression, which yielded a slightly higher treatment-related mortality rates (13.6%) than observed in the two previous studies: 7% in the GOELAMS-LTP95 trial and 3.4% in the three weekly CHOP arm of the NHL-B2 trial of DSHNHL. However, this difference requires cautious interpretation because patients from the NHL-B2 trial of DSHNHL had far better baseline patient characteristics than that of our study cohort, including substantially lower rates of BM involvement (12.9%), advanced stage (53.4%), IPI-high risk (25.3%), and extranodal sites >1 (30.9%).\n\nThe major limitations of our study include its retrospective nature and small sample size. Our approach did not include a steroid prephase, which is advocated by the German high-grade lymphoma study group and might increase patient tolerability to chemotherapy [18]. Despite these limitations, our results address a very important question pertaining to the proper dose of CHOP chemotherapy for frail elderly patients. It is especially noteworthy that the regimen did not compromise efficacy despite the dose reduction, which suggests that at least some patients can be treated with reduced dose CHOP without compromising the efficacy of this therapy. We believe that full-dose chemotherapy is not mandatory in frail elderly populations, as the outcomes of intensive chemotherapies were not more favorable than those of CHOP therapy in the MDACC study [24] or a separate randomized trial [16]. In theory, through effectively separating these two populations of patients, we may be able to discover trends towards better performance status, early stage disease, and less involvement of extranodal disease in long-term survivors.\n\nIn conclusion, the efficacy of dose-attenuated CHOP appears comparable to that of full-dose CHOP chemotherapy in elderly patients. The short duration of response with frequent relapses and a high toxicity rates remain serious shortcomings associated with this regimen. However, we identified a subgroup of long-term survivors with durable responses and strategies are required to effectively identify such patients. In addition, safer and more effective novel therapeutic approaches for elderly populations are urgently needed.\n\nAuthors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.\n\nFig. 1 Survival curves. (A) The estimated two-year progression-free survival rate was 36.7% and (B) the two-year overall survival rate was 46.6%.\nTable 1 Patient characteristics.\nAbbreviations: AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; EATL, enteropathy-associated T-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase; PIT, Prognostic Index for PTCL-U; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; WHO, World Health Organization.\n\nTable 2 Univariate analysis of prognostic factors.\nAbbreviations: AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; BM, bone marrow; EATL, enteropathy-associated T-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PIT, Prognostic Index for PTCL-U; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; WHO, World Health Organization.\n\nTable 3 Multivariate analysis of prognostic factors.\nAbbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; NA, not applicable; NS, not significant; OS, overall survival; PFS, progression-free survival.\n==== Refs\n1 Savage KJ Harris NL Vose JM ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project Blood 2008 111 5496 5504 18385450 \n2 Anderson JR Armitage JO Weisenburger DD Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project Ann Oncol 1998 9 717 720 9739436 \n3 Vose J Armitage J Weisenburger D International T-Cell Lymphoma Project International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes J Clin Oncol 2008 26 4124 4130 18626005 \n4 Gallamini A Stelitano C Calvi R Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study Blood 2004 103 2474 2479 14645001 \n5 Weisenburger DD Savage KJ Harris NL Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project Blood 2011 117 3402 3408 21270441 \n6 Schmitz N Trümper L Ziepert M Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group Blood 2010 116 3418 3425 20660290 \n7 Adams SV Newcomb PA Shustov AR Racial patterns of peripheral T-cell lymphoma incidence and survival in the United States J Clin Oncol 2016 34 963 971 26962200 \n8 Peyrade F Jardin F Thieblemont C Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial Lancet Oncol 2011 12 460 468 21482186 \n9 Extermann M Hurria A Comprehensive geriatric assessment for older patients with cancer J Clin Oncol 2007 25 1824 1831 17488980 \n10 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology. 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Results of the randomized phase III trial GOELAMS-LTP95 Br J Haematol 2010 151 159 166 20738307 \n17 Jo JC Choi Y Shin HJ Peripheral T cell lymphomas in elderly patients: a retrospective analysis from the Hematology Association of South East Korea (HASEK) Ann Hematol 2016 95 619 624 26779714 \n18 Pfreundschuh M How I treat elderly patients with diffuse large B-cell lymphoma Blood 2010 116 5103 5110 20805363 \n19 Zhao H Wang T Wang Y Comorbidity as an independent prognostic factor in elderly patients with peripheral T-cell lymphoma Onco Targets Ther 2016 9 1795 1799 27069369 \n20 Bastion Y Blay JY Divine M Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival-a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years J Clin Oncol 1997 15 2945 2953 9256139 \n21 Bertini M Freilone R Vitolo U The treatment of elderly patients with aggressive non-Hodgkin's lymphomas: feasibility and efficacy of an intensive multidrug regimen Leuk Lymphoma 1996 22 483 493 8882962 \n22 Grigg A Solal-Celigny P Hoskin P Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin's lymphoma Leuk Lymphoma 2003 44 1503 1508 14565651 \n23 Lyman GH Kuderer N Agboola O Balducci L Evidence-based use of colony-stimulating factors in elderly cancer patients Cancer Control 2003 10 487 499 14652525 \n24 Escalón MP Liu NS Yang Y Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M.D. Anderson Cancer Center experience Cancer 2005 103 2091 2098 15816054\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2287-979X", "issue": "52(4)", "journal": "Blood research", "keywords": "Dose-attenuated CHOP; Elderly; Peripheral T cell lymphoma", "medline_ta": "Blood Res", "mesh_terms": null, "nlm_unique_id": "101605247", "other_id": null, "pages": "270-275", "pmc": null, "pmid": "29333403", "pubdate": "2017-12", "publication_types": "D016428:Journal Article", "references": "8141877;20660290;15016643;8882962;17242396;25113753;26962200;15816054;18385450;9256139;18626005;9739436;27069369;14565651;14645001;20738307;14652525;20805363;17488980;21270441;26779714;21482186", "title": "Treatment outcomes of dose-attenuated CHOP chemotherapy in elderly patients with peripheral T cell lymphoma.", "title_normalized": "treatment outcomes of dose attenuated chop chemotherapy in elderly patients with peripheral t cell lymphoma" }	[ { "companynumb": "KR-PFIZER INC-2018003488", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 2X/DAY (FOR FIVE DAYS, CYCLIC)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PERIPHERAL T-CELL LYMPHOMA UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.4 MG/M2, CYCLIC (FOR 1 DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PERIPHERAL T-CELL LYMPHOMA UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.4", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG/M2, CYCLIC (FOR 1 DAY) 25% REDUCTION FROM FULL-DOSE CHOP", "drugenddate": null, "drugenddateformat": null, "drugindication": "PERIPHERAL T-CELL LYMPHOMA UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "562.5 MG/M2, CYCLIC (FOR ONE DAY) (25% REDUCTION FROM FULL-DOSE CHOP", "drugenddate": null, "drugenddateformat": null, "drugindication": "PERIPHERAL T-CELL LYMPHOMA UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "562.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "CHOI, E.. TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. BLOOD RESEARCH. 2017?52 (4):270-275", "literaturereference_normalized": "treatment outcomes of dose attenuated chop chemotherapy in elderly patients with peripheral t cell lymphoma", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14368030, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]
{ "abstract": "BACKGROUND Epinephrine for anaphylactic shock is the standard life-saving treatment in the emergency department. Cardiac symptoms after epinephrine administration in a child with no prior cardiac history are often not suspected. We describe a presentation of diastolic cardiac dysfunction after anaphylaxis from a bee sting in an adolescent male. CASE REPORT A 16-year-old male with no prior history of allergy presented with anaphylaxis following a bee sting. The patient received an inadvertent intravenous rather than intramuscular dose of 1: 1000 epinephrine, leading to myocardial ischemia. Diastolic dysfunction resulting from myocardial ischemia and fluid resuscitation led to development of pulmonary edema. The patient required epinephrine drip for hemodynamic support and BiPAP for respiratory support. CONCLUSIONS This case highlights the risk of giving a rapid intravenous push of epinephrine, which converted an anaphylactic reaction to cardiogenic shock. Anaphylaxis-related coronary ischemia (Kounis) syndrome is another less likely etiology for our patient's presentation.", "affiliations": "Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Cardiology, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.", "authors": "Tripathi\|Sandeep\|S\|;Kulikowska\|Agnieszka\|A\|;Patel\|Priti M\|PM\|;Hassan\|Nabil E\|NE\|", "chemical_list": "D014662:Vasoconstrictor Agents; D004837:Epinephrine", "country": "United States", "delete": false, "doi": "10.12659/AJCR.922120", "fulltext": null, "fulltext_license": null, "issn_linking": "1941-5923", "issue": "21()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000293:Adolescent; D000707:Anaphylaxis; D000818:Animals; D001516:Bees; D004562:Electrocardiography; D004837:Epinephrine; D006801:Humans; D007275:Injections, Intravenous; D007299:Insect Bites and Stings; D008297:Male; D017202:Myocardial Ischemia; D011654:Pulmonary Edema; D012770:Shock, Cardiogenic; D014662:Vasoconstrictor Agents", "nlm_unique_id": "101489566", "other_id": null, "pages": "e922120", "pmc": null, "pmid": "32467557", "pubdate": "2020-05-29", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute Myocardial Ischemia Following Bee Sting in an Adolescent Male: A Case Report.", "title_normalized": "acute myocardial ischemia following bee sting in an adolescent male a case report" }	[ { "companynumb": "US-PFIZER INC-2020322892", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAPHYLACTIC REACTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UP-TITRATED UP TO 0.1 MCG/KG/MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAPHYLACTIC REACTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "50 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD BITE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL ISCHAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN (E.C.)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MG OF 1: 1000 EPINEPHRINE BY RAPID PUSH", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD STING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "56.7", "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TRIPATHI, S.. ACUTE MYOCARDIAL ISCHEMIA FOLLOWING BEE STING IN AN ADOLESCENT MALE: A CASE REPORT. 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0.3 SHOULD HAVE BEEN ADMINISTERED VIA THE IM ROUTE; INSTEAD ADMINISTERED VIA THE IV ROUTE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD STING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAPHYLACTIC REACTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "019430", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "0.3 MILLIGRAM 1:1000 (WHICH IS THE IM DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD STING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "50 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD BITE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "56.7", "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TRIPATHI S, KULIKOWSKA A, PATEL PM, HASSAN NE. ACUTE MYOCARDIAL ISCHEMIA FOLLOWING BEE STING IN AN ADOLESCENT MALE: A CASE REPORT. AM?J?CASE?REP 2020?21:E922120.", "literaturereference_normalized": "acute myocardial ischemia following bee sting in an adolescent male a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200820", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177616, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-AMNEAL PHARMACEUTICALS-2020-AMRX-01739", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "020800", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.3 MILLIGRAM, 1:1000", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAPHYLACTIC REACTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRENACLICK" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020800", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.1 MICROGRAM/KILOGRAM, EVERY HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".1", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRENACLICK" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAPHYLACTIC REACTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "020800", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.1 MICROGRAM/KILOGRAM, EVERY MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "806", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".1", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRENACLICK" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "56.7", "reaction": [ { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TRIPATHI S, KULIKOWSKA A, PATEL PM, HASSAN NE. ACUTE MYOCARDIAL ISCHEMIA FOLLOWING BEE STING IN AN ADOLESCENT MALE: A CASE REPORT. AM J CASE REP. 2020?21:E922120", "literaturereference_normalized": "acute myocardial ischemia following bee sting in an adolescent male a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200619", "receivedate": "20200619", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17917600, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]
{ "abstract": "BACKGROUND Pancreatic metastasis from colorectal cancer is rare and can masquerade as primary pancreatic cancer. CASE REPORT A 70-year-old male was diagnosed with advanced rectal cancer with multiple liver metastases. After neoadjuvant chemotherapy, he underwent radical surgery for the primary tumor and hepatectomy for multiple liver metastases. Adjuvant chemotherapies and additional surgeries were subsequently required for recurrences in the liver, lung, and lymph nodes. A diffuse hypovascular nodule in the pancreatic head and a solitary liver metastasis were detected 2.5 years after the initial surgery and he accordingly underwent further chemotherapy. However, the pancreatic tumor progressed, invading the pancreatic duct and biliary tract. Obstructive jaundice finally prompted discontinuation of chemotherapy and he underwent biliary drainage. His diffuse and hypovascular tumor was clinically and radiographically diagnosed as a primary pancreatic cancer. Pancreatic resection for the pancreatic tumor and hepatectomy for the liver metastasis were performed 4.2 years after the initial surgery, achieving radiographic and surgical curative resection. Pathological examination of the surgical specimen resulted in a definitive diagnosis of metachronous pancreatic metastasis from his primary rectal cancer. Despite further chemotherapy, his general condition worsened; however, he remains alive 5.4 years after the initial surgery, with best supportive care. CONCLUSIONS Pancreatic metastasis originating from rectal cancer can masquerade as primary pancreatic cancer clinically and radiologically. Multimodality treatment is mandatory for metastatic colorectal cancer. Aggressive surgeries for pancreatic metastasis should be considered if curative resection appears possible radiographically and/or intraoperatively.", "affiliations": "Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.", "authors": "Tani\|Ryotaro\|R\|;Hori\|Tomohide\|T\|;Yamada\|Masahiro\|M\|;Yamamoto\|Hidekazu\|H\|;Harada\|Hideki\|H\|;Yamamoto\|Michihiro\|M\|;Yazawa\|Takefumi\|T\|;Tani\|Masaki\|M\|;Kamada\|Yasuyuki\|Y\|;Aoyama\|Ryuhei\|R\|;Sasaki\|Yudai\|Y\|;Zaima\|Masazumi\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.12659/AJCR.918669", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3178450310.12659/AJCR.918669918669ArticlesMetachronous Pancreatic Metastasis from Rectal Cancer that Masqueraded as a Primary Pancreatic Cancer: A Rare and Difficult-to-Diagnose Metastatic Tumor in the Pancreas Tani Ryotaro BCDHori Tomohide ACDEFYamada Masahiro BCDYamamoto Hidekazu FHarada Hideki FYamamoto Michihiro FYazawa Takefumi FTani Masaki FKamada Yasuyuki FAoyama Ryuhei FSasaki Yudai FZaima Masazumi ADFDepartment of Surgery, Shiga General Hospital, Moriyama, Shiga, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Ryotaro Tani and Tomohide Hori contributed equally to this work\n\nConflict of interest: None declared\n\nCorresponding Author: Tomohide Hori, e-mail: horitomo55office@yahoo.co.jp2019 30 11 2019 20 1781 1787 11 7 2019 24 9 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 70\n\nFinal Diagnosis: Metachronous pancreatic metastasis\n\nSymptoms: None\n\nMedication: —\n\nClinical Procedure: Surgery\n\nSpecialty: Gastroenterology and Hepatology\n\nObjective:\nRare disease\n\nBackground:\nPancreatic metastasis from colorectal cancer is rare and can masquerade as primary pancreatic cancer.\n\nCase Report:\nA 70-year-old male was diagnosed with advanced rectal cancer with multiple liver metastases. After neoadjuvant chemotherapy, he underwent radical surgery for the primary tumor and hepatectomy for multiple liver metastases. Adjuvant chemotherapies and additional surgeries were subsequently required for recurrences in the liver, lung, and lymph nodes. A diffuse hypovascular nodule in the pancreatic head and a solitary liver metastasis were detected 2.5 years after the initial surgery and he accordingly underwent further chemotherapy. However, the pancreatic tumor progressed, invading the pancreatic duct and biliary tract. Obstructive jaundice finally prompted discontinuation of chemotherapy and he underwent biliary drainage. His diffuse and hypovascular tumor was clinically and radiographically diagnosed as a primary pancreatic cancer. Pancreatic resection for the pancreatic tumor and hepatectomy for the liver metastasis were performed 4.2 years after the initial surgery, achieving radiographic and surgical curative resection. Pathological examination of the surgical specimen resulted in a definitive diagnosis of metachronous pancreatic metastasis from his primary rectal cancer. Despite further chemotherapy, his general condition worsened; however, he remains alive 5.4 years after the initial surgery, with best supportive care.\n\nConclusions:\nPancreatic metastasis originating from rectal cancer can masquerade as primary pancreatic cancer clinically and radiologically. Multimodality treatment is mandatory for metastatic colorectal cancer. Aggressive surgeries for pancreatic metastasis should be considered if curative resection appears possible radiographically and/or intraoperatively.\n\nMeSH Keywords:\nColorectal NeoplasmsNeoplasm MetastasisPancreasRectal Neoplasms\n==== Body\nBackground\nThere are various types of primary cancers of the pancreas, some of which are rare [1]. Invasive ductal carcinoma, the most common type of primary pancreatic cancer [1], usually shows as a diffuse and hypovascular nodule in imaging studies. Infiltrating carcinoma is often accompanied by invasions of the blood vessels, biliary tract, and pancreatic duct. Obstructive jaundice and associated pancreatitis frequently complicate invasive tumors located in the pancreatic head [1].\n\nMetastases to the pancreas account for approximately 2% of pancreatic neoplasms [2]. Pancreatic metastases from colorectal cancer are rare [3–14], and acceptable outcomes can be achieved by curative resection in carefully selected patients [5,6,8,10,12–15]. Treatment guidelines recommend aggressive resection of hematogenous metastases (i.e., lung or liver metastases) [16,17] if radiographic and/or surgical R0 (i.e., radiographic/surgical R0 resection, according to the Japanese Classification of Colorectal, Appendiceal and Anal carcinoma [18]) is accomplished [5,7–10,12,13,15–17]. Whether pancreatic metastases occur via hematogenous pathways is controversial [7–10,12]. Aggressive surgery should be a component of multimodality treatment of metastatic colorectal cancer [5,6,8–10,12–17].\n\nHere, we report a rare and misdiagnosed case of pancreatic metastasis originating from rectal cancer. Imaging findings resembled those of primary pancreatic cancer. We also discuss the role of surgical resection in treatment of this rare metastasis.\n\nCase Report\nA 70-year-old male visited our hospital with symptoms of bowel obstruction. Colorectal endoscopy, pathological diagnosis based on biopsy specimen, and enhanced computed tomography were performed as initial diagnostic workup. Detailed examination resulted in a clinical diagnosis of advanced rectal cancer with multiple liver metastases. He underwent neoadjuvant chemotherapy with 3 courses of 5-fluorouracil plus oxaliplatin followed by 2 courses of panitumumab followed by laparoscopic low anterior resection with intentional lymphadenectomy. Partial hepatectomy and left lobectomy were also performed for multiple liver metastases. According to imaging studies and surgical findings, curative resection was achieved (i.e., radiographic/surgical R0 resection [18]). The final pathological diagnosis was T4aN1aM1a stage IVA (TNM classification [19]) well-differentiated tubular adenocarcinoma. Adjuvant chemotherapy with 6 courses of 5-fluorouracil plus oxaliplatin was completed. One year after the initial surgery, lymphadenectomy for recurrent metastatic lymph nodes was required, achieving radiographic/surgical R0 [18]; thereafter, further chemotherapy with capecitabine plus panitumumab was administered. Subsequently, right lower lobectomy was performed for a solitary lung metastasis and chemotherapy discontinued for 7 months because radiographic/surgical R0 [18] had been achieved. A solitary liver metastasis and lymphoid metastases were then detected; these resolved radiographically after recommencing chemotherapy with 5-fluorouracil, oxaliplatin and panitumumab. This was discontinued once radiographic R0 [18] had again been achieved, and then resumed after detection of another solitary liver metastasis and lymphoid metastasis. Oxaliplatin was omitted from his regimen because of refractory peripheral neuropathy. Four cycles of chemotherapy with 5-fluorouracil plus leucovorin were administered, achieving radiological resolution of these metastases (radiographic R0 [18]). At 2.5 years after the initial surgery, a further solitary liver metastasis and a diffuse hypovascular nodule in the pancreatic head were detected (Figure 1). Further chemotherapy with 5-fluorouracil, irinotecan and bevacizumab was administered for 1.6 years, and then discontinued because of development of progressive obstructive jaundice caused by the pancreatic tumor. Radiographic and ultrasonography details of this pancreatic neoplasm are shown in Figures 2–4. The tumor was in the pancreatic head, hypovascular, and 21×19 mm in size (Figures 1, 2). Diffuse invasion of the pancreatic duct and biliary tract resulted in obstruction and remarkable dilation of the distal pancreatic duct, intrahepatic bile ducts, and extrahepatic biliary tract (Figures 3, 4). Biliary drainage was achieved via an endoscopic nasobiliary drainage tube (Figure 4). Pathological examination of a biopsy specimen resulted in a diagnosis of moderately-differentiated tubular adenocarcinoma. It was difficult to make a definitive diagnosis of our patient’s locally advanced pancreatic tumor; however, we concluded on the basis of the clinical and radiographic evidence that it was a primary pancreatic cancer rather than a metachronous metastasis from the original rectal cancer. At 4.2 years after the initial surgery, subtotal stomach-preserving pancreaticoduodenectomy for the pancreatic tumor and partial hepatectomy for the solitary liver metastasis were performed, achieving radiographic/surgical R0 resection [18]. Pathological examination revealed that the pancreatic tumor was similar to the original rectal cancer (Figure 5); furthermore, the pancreatic neoplasm lacked the typical pathological features (e.g., not a tubular adenocarcinoma) of primary pancreatic cancer. Immunohistological studies revealed negativity for cytokeratin 7 and positivity for cytokeratin 20 and caudal type homeobox transcription factor 2 (Figure 6). These findings resulted in a definitive pathological diagnosis of metachronous pancreatic metastasis originating from our patient’s primary rectal cancer. A total of 6 courses of chemotherapy with 5-fluorouracil, panitumumab and leucovorin were given; however, multiple liver metastases appeared. His general condition worsened despite further chemotherapy with 5-fluorouracil, panitumumab and leucovorin and with 5-fluorouracil, irinotecan and bevacizumab. Although a regimen switch to trifluridine and tipiracil hydrochloride was considered, he opted for best supportive care at 4.8 years after the initial surgery. Carcinomatous ascites has been well controlled, and he remains alive 5.4 years after the initial surgery. Time course of this patient (e.g., surgical resections and chemotherapy regimens) was summarized in Figure 7.\n\nDiscussion\nThe primary cancers that are most frequently responsible for pancreatic metastases are reportedly renal cell carcinoma (54.3–83.3%) and rectal cancer (7.5–16.7%) [2,9,12,20]. The median interval between resection of the primary cancer and development of pancreatic metastases is relatively longer, being reportedly 32.5–157 months [5,7–9,20]. Pancreatic metastases appearing long after the initial surgery (>5 years) have been documented [4]. However, T1 colorectal cancers according to TNM classification [19] (i.e., oncological depth within submucosal layer) rarely cause pancreatic metastases [9].\n\nAccurate preoperative diagnosis of pancreatic metastasis rather than a primary pancreatic cancer is difficult [7–10,12]. Cytological examination of a fine needle aspirate or pathological examination of a biopsy specimen obtained under endoscopic ultrasonography guidance is useful for preoperative diagnosis [4,8,9,20,21]. In our case, although pathological assessment of a biopsy specimen suggested moderately-differentiated tubular adenocarcinoma, it was not possible to make a definite preoperative diagnosis of pancreatic metastasis originating from rectal cancer, which was regrettable given the impact the diagnosis made on subsequent management. Unfortunately, the clinical features, particularly the findings on imaging studies (e.g., obstructive jaundice with biliary dilatation and associated pancreatitis with dilated pancreatic duct), misled us into diagnosing primary pancreatic cancer. It must always be kept in mind that a pancreatic metastasis may closely resemble the more common primary pancreatic tumor. Only 1.3% of pancreatic metastases originate from colorectal cancer [7] and the pancreas is a very rare site for metastases from colorectal cancer [3–13]; thus, the statistical unlikelihood of metastasis was a factor in our preoperative misdiagnosis.\n\nThe usefulness of immunohistological staining for cytokeratin 7, cytokeratin 20, and caudal type homeobox transcription factor 2 is well-documented [4,7,9,14]. Negativity for cytokeratin 7 and positivity for cytokeratin 20 favor colorectal cancer over primary pancreatic cancer [7,9]; however, immunohistological assessment is not practicable as an intraoperative diagnostic tool. Although thyroid transcription factor 1 specifically expresses in most thyroid tumors and in a significant subset of pulmonary neoplasms [22], combinations of cytokeratin 7, cytokeratin 20, and caudal type homeobox transcription factor 2 are not specific for colorectal cancer.\n\nOptimal treatment for pancreatic metastasis has not yet been established [5,8,10,15,20]. Pancreatic resection may confer a survival benefit on patients with pancreatic metastases [2,5–10,12–15,20], the 5-year survival rate after this procedure reportedly being approximately 30% [23]. Cases of successfully resected pancreatic metastases from colorectal cancer after multiple resections of metastatic lesions have been reported [2,5–10,12–14,24]. Thus, patients who are fit for surgery and free of metastases in other organs should be considered good candidates for pancreatic resection [2,5–10,12–14,24].\n\nThe role of intentional lymphadenectomy in patients with pancreatic metastases is controversial [10,12,23]; pancreatic metastasis may be accompanied by lymphoid metastases in regional lymph nodes [8,23]. The mortality and morbidity rates for pancreatic resections including pancreaticoduodenectomy for pancreatic metastasis are reportedly 1.4% and 48.3%, respectively [2]. Simple pancreatic resection without intentional dissection of lymph nodes and nerve plexus is currently considered safe and feasible [25]; intentional lymphadenectomy increases the risk of pancreatic leakage [25].\n\nPancreatic cancer is a solid cancer with a poor prognosis [1]; pancreatic metastases also have a poor prognosis (8.7 months) [10]. In the absence of a definitive diagnosis of pancreatic metastasis, it is not possible to select the optimal chemotherapy regimen [13,26]. From the viewpoint of therapeutic strategy, surgical resection of a pancreatic mass is justified not only to make a definitive diagnosis [8,13,26] but also to improve survival [2,5,6,8–10,12–15,20]. The overall survival of patients with stage IV colorectal cancer is approximately 9 months if chemotherapy is not administered after primary resection [17]. Multimodality therapy is crucial for stage IV colorectal cancer [16,17]. As in our case, aggressive treatment aimed at achieving radiographic and/or surgical R0 should be repeatedly administered to patients with colorectal cancer when they develop recurrences and metastases.\n\nConclusions\nMetachronous pancreatic metastasis originating from rectal cancer can masquerade clinically and radiographically as a primary pancreatic cancer. The possibility of a rare, easily misdiagnosed metastatic tumor in the pancreas must always be kept in mind. Aggressive surgery for pancreatic metastases is justified, not only to make a definitive diagnosis to inform selection of subsequent chemotherapy but also to improve survival, even in the presence of recurrences and metastases provided radiographic and/or surgical curative resection can be accomplished.\n\nWe are grateful to Yoshihiro Yamamoto and Masayuki Shintaku (Department of Pathology, Shiga General Hospital, Moriyama, Japan) for their assistance with the histopathological and immunopathological assessments.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Findings on dynamic computed tomography (CT). At 2.5 years after the initial surgery, a diffuse and low-density nodule (yellow arrows) was detected in the pancreatic head. This hypovascular nodule shows no enhancement on dynamic CT. The distal pancreatic duct is dilated and there is evidence of associated pancreatitis.\n\nFigure 2. Findings on endoscopic ultrasonography. The low echoic and diffuse nodule (A) (yellow arrows) was 21×19 mm in size and Doppler ultrasonography (B) revealed that it was hypovascular.\n\nFigure 3. The finding on magnetic resonance imaging. The finding on magnetic resonance cholangiopancreatography is shown. The distal pancreatic duct, intrahepatic bile ducts, and extrahepatic biliary tract are remarkably dilated as a result of obstruction in the pancreatic head.\n\nFigure 4. The finding on endoscopic retrograde cholangiopancreatography and biliary drainage by nasobiliary drainage tube. The finding on endoscopic retrograde cholangiopancreatography is shown (A). The resultant obstructive jaundice was progressive and biliary drainage was required. A nasobiliary drainage tube was placed endoscopically (B).\n\nFigure 5. Histopathological assessment. Pathological findings on hematoxylin-eosin stained sections are shown (100×). The pathological features of the rectal cancer (A) and pancreatic neoplasm (B) are similar.\n\nFigure 6. Immunohistological studies. Pathological finding on hematoxylin-eosin staining (A) and immunohistological findings on cytokeratin 7 (B), cytokeratin 20 (C), and caudal type homeobox transcription factor 2 (D) in the pancreatic tumor were shown (20×).\n\nFigure 7. Time course of this patient. Time course of this patient (e.g., surgical resections and chemotherapy regimens) was summarized.\n==== Refs\nReferences:\n1. Kamisawa T Wood LD Itoi T Takaori K Pancreatic cancer Lancet 2016 388 73 85 26830752 \n2. Huang Q Zhou H Liu C Surgical resection for metastatic tumors in the pancreas: A single-center experience and systematic review Ann Surg Oncol 2019 26 1649 56 30924017 \n3. Greve E Dumas O Fumex F Solitary pancreatic metastasis four years after curative treatment for rectal carcinoma Gastroenterol Clin Biol 2008 32 258 60 18456107 \n4. Sano I Katanuma A Yane K Pancreatic metastasis from rectal cancer that was diagnosed by endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) Intern Med 2017 56 301 5 28154274 \n5. Sperti C Pasquali C Berselli M Metastasis to the pancreas from colorectal cancer: Is there a place for pancreatic resection? Dis Colon Rectum 2009 52 1154 59 19581861 \n6. Hino H Kagawa H Kinugasa Y Long-term survival with surgery for metachronous retroperitoneal lymph node and pancreatic metastases after curative resection of rectal cancer: a case report Surg Case Rep 2016 2 49 27225417 \n7. Yamaguchi T Takii Y Maruyama S [Four cases of resectable metastatic pancreatic cancer from colorectal cancers] The Japanese Journal of Gastroenterological Surgery 2012 45 740 48 [in Japanese] \n8. Okumura S Yoshimura T Fujita K [A case of metachronous metastasis to the pancreas from rectal cancer] Journal of the Japan Pancreas Society 2014 29 253 62 [in Japanese] \n9. Sakon M Hamada J Sekino Y [A case of metachronous metastasis of the pancreas from rectal cancer] Journal of the Japan Pancreas Society 2008 23 748 54 [in Japanese] \n10. Ishigure K Kawase Y Kanazumi N [Report of three resected cases of pancreatic metastatic tumors] The Japanese Journal of Gastroenterological Surgery 2000 33 1686 90 [in Japanses] \n11. Bachmann J Michalski CW Bergmann F Metastasis of rectal adenocarcinoma to the pancreas. Two case reports and a review of the literature JOP 2007 8 214 22 17356246 \n12. Tatsuzawa Y Kurokawa M Mochiki Y [A case of pancreatic metastasis from colorectal cancer] The Japanese Journal of Gastroenterological Surgery 2001 34 132 36 \n13. Lee CW Wu RC Hsu JT Isolated pancreatic metastasis from rectal cancer: A case report and review of literature World J Surg Oncol 2010 8 26 20374636 \n14. Matsubara N Baba H Okamoto A Rectal cancer metastasis to the head of the pancreas treated with pancreaticoduodenectomy J Hepatobiliary Pancreat Surg 2007 14 590 94 18040627 \n15. You DD Choi DW Choi SH Surgical resection of metastasis to the pancreas J Korean Surg Soc 2011 80 278 82 22066048 \n16. Lintoiu-Ursut B Tulin A Constantinoiu S Recurrence after hepatic resection in colorectal cancer liver metastasis – Review article J Med Life 2015 8 12 14 \n17. Japanese Society for Cancer of the Colon and Rectum JSCCR guidelines 2019 for the treatment of colorectal cancer Tokyo Kanehara 2019 \n18. Japanese Society for Cancer of the Colon and Rectum Japanese classification of colorectal, appendiceal and anal carcinoma 9th edition Tokyo Kanehara 2018 \n19. Union for International Cancer Control TNM classification of malignant tumors 8th edition New York Wiley Blackwell 2017 \n20. Endo Y Noda H Watanabe F A retrospective analysis of preoperative evaluation and surgical resection for metastatic tumors of the pancreas Indian J Surg Oncol 2019 10 251 57 31168244 \n21. Hussain T Salamat A Farooq MA Indications for endoscopic ultrasound and diagnosis on fine-needle aspiration and cytology J Coll Physicians Surg Pak 2009 19 223 27 19356336 \n22. Aversa S Bellan C TTF1 expression in pulmonary metastatic rectal adenocarcinoma Case Rep Gastrointest Med 2018 2018 6405125 30631609 \n23. Reddy S Wolfgang CL The role of surgery in the management of isolated metastases to the pancreas Lancet Oncol 2009 10 287 93 19261257 \n24. Saito M Teranishi F Shibata T [A case of resected pancreatic metastasis of rectal cancer after multiple resections of metastatic lesions] Gan To Kagaku Ryoho 2019 46 327 29 [in Japanese] 30914549 \n25. Hori T Yamamoto H Harada H Inferior pancreaticoduodenal artery aneurysm related with groove pancreatitis persistently repeated hemosuccus pancreaticus even after coil embolization Am J Case Rep 2019 20 567 74 31006768 \n26. Yabe N Murai S Ozawa H [A case of unresectable advanced rectal cancer with a pancreatic tumor that was successfully treated with FOLFIRINOX] Gan To Kagaku Ryoho 2016 43 2468 70 28133357\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "20()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000368:Aged; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D012004:Rectal Neoplasms", "nlm_unique_id": "101489566", "other_id": null, "pages": "1781-1787", "pmc": null, "pmid": "31784503", "pubdate": "2019-11-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31168244;18040627;26361505;26830752;27225417;30631609;19356336;17356246;19261257;30924017;30914549;28133357;28154274;18456107;22066048;20374636;19581861;31006768", "title": "Metachronous Pancreatic Metastasis from Rectal Cancer that Masqueraded as a Primary Pancreatic Cancer: A Rare and Difficult-to-Diagnose Metastatic Tumor in the Pancreas.", "title_normalized": "metachronous pancreatic metastasis from rectal cancer that masqueraded as a primary pancreatic cancer a rare and difficult to diagnose metastatic tumor in the pancreas" }	[ { "companynumb": "JP-PFIZER INC-2020033890", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PANITUMUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": 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null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TANI, R.. METACHRONOUS PANCREATIC METASTASIS FROM RECTAL CANCER THAT MASQUERADED AS A PRIMARY PANCREATIC CANCER: A RARE AND DIFFICULT-TO- DIAGNOSE METASTATIC TUMOR IN THE PANCREAS. 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{ "abstract": "Background: Patients with chronic obstructive pulmonary disease have a high prevalence of osteoporosis, and different osteoporosis drugs are used to prevent fractures in these patients. Although the overall incidence of complete or incomplete, atypical femoral fracture (AFF) is low, long-term use of antiresorptive agents is associated with an increased risk of developing AFF. Methods: We present a patient with chronic obstructive pulmonary disease with recurrent symptoms of an incomplete AFF who had been treated with glucocorticoids, and sequentially with alendronate, zoledronic acid, strontium ranelate, raloxifene, denosumab and finally with teriparatide. The first episode occurred before osteoporosis therapies, the second after bisphosphonate treatments, and the third under denosumab. Results: Although her symptoms resolved along with gradually healing of fracture lines after conservative treatment without surgical intervention, progressive varus deformity of the proximal femur may have contributed to recurrence of AFF. Conclusion: Early treatment with anabolic agents and prophylactic fixation of incomplete AFF may alleviate symptoms and prevent recurrences.", "affiliations": "Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopaedic Surgery, National Taiwan University Hospital , Taipei Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.", "authors": "Lai\|Kun-Hung\|KH\|;Chiang\|Chih-Yung\|CY\|;Yang\|Rong-Sen\|RS\|https://orcid.org/0000-0002-0979-4463;Yang\|Kai-Chiang\|KC\|https://orcid.org/0000-0002-0979-4463;Wu\|Chang-Chin\|CC\|https://orcid.org/0000-0002-9309-5824", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005938:Glucocorticoids; D000069448:Denosumab", "country": "England", "delete": false, "doi": "10.1080/17843286.2018.1534576", "fulltext": null, "fulltext_license": null, "issn_linking": "1784-3286", "issue": "74(5)", "journal": "Acta clinica Belgica", "keywords": "Chronic obstructive pulmonary disease; atypical femoral fracture; bisphosphonate; denosumab; glucocorticoid; incomplete", "medline_ta": "Acta Clin Belg", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D000072700:Conservative Treatment; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D017102:Fracture Healing; D005938:Glucocorticoids; D006801:Humans; D010024:Osteoporosis; D029424:Pulmonary Disease, Chronic Obstructive; D012008:Recurrence", "nlm_unique_id": "0370306", "other_id": null, "pages": "370-374", "pmc": null, "pmid": "30336748", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Conservative treatment of recurrent symptoms of an incomplete, atypical femoral fracture associated with glucocorticoid, bisphosphonate, and denosumab therapy in a patient with chronic obstructive pulmonary disease.", "title_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease" }	[ { "companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-222825", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "STRONTIUM RANELATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, 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"drugtreatmentdurationunit": null, "medicinalproduct": "FORTEO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM\\CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSAMAX PLUS D" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACLASTA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROLIA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI K-H, CHIANG C-Y, YANG R-S, YANG K-C, WU C-C. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLIN BELG. 2019?74 (5):370 374", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20191016", "receivedate": "20191005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16887687, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TW-BAUSCH-BL-2018-031522", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR LONG TIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200307" } }, "primarysource": { "literaturereference": "LAI K, CHIANG C, YANG R, WU C. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLINICA BELGICA. INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE. 2018?.", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181116", "receivedate": "20181116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15628032, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PHHY2018TW156305", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "STRONTIUM RANELATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "STRONTIUM RANELATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERIPARATIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERIPARATIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RALOXIFENE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALOXIFENE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DENOSUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD (FOR LONG TIME)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200307" } }, "primarysource": { "literaturereference": "LAI KH, CHIANG CY, YANG RS, YANG KC, WU CC. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLINICA BELGICA: INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE. 2018", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181120", "receivedate": "20181120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15641310, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "We present a report of what we believe was an extremely rare case of hyperacute respiratory failure caused by first time exposure to cyclophosphamide in a 40-year-old woman with systemic lupus erythematosus. The patient was extensively evaluated for alternative etiologies with negative results. Treatment with methylprednisolone and high doses of human immunoglobulin resulted in gradual improvement of the patient's condition. We review the literature with regard to cyclophosphamide-induced lung toxicity.", "affiliations": "Department of Nephrology, Aalborg University Hospital, Mølleparkvej 4, 9000, Aalborg, Denmark, pschjelderup@gmail.com.", "authors": "Schjelderup\|P\|P\|;El-Galaly\|T C\|TC\|;Frøkjær\|J B\|JB\|;Ring\|T\|T\|", "chemical_list": "D018501:Antirheumatic Agents; D007136:Immunoglobulins; D003520:Cyclophosphamide; D008775:Methylprednisolone", "country": "Germany", "delete": false, "doi": "10.1007/s00393-014-1381-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0340-1855", "issue": "73(10)", "journal": "Zeitschrift fur Rheumatologie", "keywords": null, "medline_ta": "Z Rheumatol", "mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007261:Infusions, Intra-Arterial; D008180:Lupus Erythematosus, Systemic; D008775:Methylprednisolone; D012128:Respiratory Distress Syndrome; D016896:Treatment Outcome", "nlm_unique_id": "0414162", "other_id": null, "pages": "939-41", "pmc": null, "pmid": "24830677", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19786984;9415567;20692540;6809197;12209517;781905;9625032;1068740;8970380", "title": "Acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus.", "title_normalized": "acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus" }	[ { "companynumb": "PHHY2015DK103564", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOL FOR INF", "drugdosagetext": "250 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary toxicity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SCHJELDERUP P, EL-GALAY TC, FROKJAER JB, RING T. ACUTE RESPIRATORY FAILURE DURING FIRST CYCLOPHOSPHAMIDE INFUSION IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS. Z-RHEUMATOL. 2014;73:939-41", "literaturereference_normalized": "acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20150901", "receivedate": "20150901", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11442803, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" } ]
{ "abstract": "BACKGROUND\nDermatomyositis is an autoimmune disease of unknown etiology characterized by inflammation of the skin and muscles. Several medications have been implicated in the development of dermatomyositis; however, the disease has rarely been linked to the use of tumor necrosis factor (TNF) inhibitors. We report 4 cases of dermatomyositis that developed or were exacerbated by exposure to the TNF inhibitors etanercept and adalimumab. Observation Four patients with symptoms of inflammatory arthritis were treated with TNF inhibitors for a duration ranging from 2 months to 2 years. All 4 patients developed symptoms consistent with dermatomyositis, including inflammatory rash and muscle weakness. Their symptoms persisted after discontinuation of the treatment with the TNF inhibitors but responded to treatment with corticosteroids and immunosuppressive medications.\n\n\nCONCLUSIONS\nTumor necrosis factor inhibitors have been associated with the onset of a number of autoimmune disorders, most commonly vasculitis and a lupuslike syndrome. Rarely have they been associated with dermatomyositis. The 4 cases reported herein indicate that TNF inhibitor use can be associated with either induction or exacerbation of dermatomyositis.", "affiliations": "Department of Medicine, Division of Rheumatology, University of Pennsylvania School of Medicine, Perelman Center for Advanced Medicine, First Floor South Pavilion, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.", "authors": "Klein\|Rachel\|R\|;Rosenbach\|Misha\|M\|;Kim\|Ellen J\|EJ\|;Kim\|Brian\|B\|;Werth\|Victoria P\|VP\|;Dunham\|Jonathan\|J\|", "chemical_list": "D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept", "country": "United States", "delete": false, "doi": "10.1001/archdermatol.2010.142", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-987X", "issue": "146(7)", "journal": "Archives of dermatology", "keywords": null, "medline_ta": "Arch Dermatol", "mesh_terms": "D000328:Adult; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D015551:Autoimmunity; D003882:Dermatomyositis; D003937:Diagnosis, Differential; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0372433", "other_id": null, "pages": "780-4", "pmc": null, "pmid": "20644041", "pubdate": "2010-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10580639;17632266;15158749;18625537;16705109;15899052;17763410;8960740;12796126;17139649;10399751;11055823;19416947;19028367;12506773;16960940;18272672;10579123;15996057;11762947;15297281;15852401;11256887", "title": "Tumor necrosis factor inhibitor-associated dermatomyositis.", "title_normalized": "tumor necrosis factor inhibitor associated dermatomyositis" }	[ { "companynumb": "US-AMGEN-USASP2019145492", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETANERCEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETANERCEPT" } ], "patientagegroup": "5", "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fibromyalgia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ELLEN J K.. TUMOR NECROSIS FACTOR INHIBITOR-ASSOCIATED DERMATOMYOSITIS. ARCHIVES OF DERMATOLOGY. 2010?146 (7):780-784", "literaturereference_normalized": "tumor necrosis factor inhibitor associated dermatomyositis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16789138, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-AMGEN-USASP2019145569", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETANERCEPT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETANERCEPT" } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aldolase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rheumatoid factor increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Antinuclear antibody increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Photosensitivity reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIM ELLEN J.. TUMOR NECROSIS FACTOR INHIBITOR-ASSOCIATED DERMATOMYOSITIS. ARCHIVES OF DERMATOLOGY. 2010?146 (7):780-784", "literaturereference_normalized": "tumor necrosis factor inhibitor associated dermatomyositis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16789201, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "In this nationwide population-based study, we examined whether haloperidol exposure is associated with a higher risk of mortality than are other antipsychotic medications. Patients who newly received monotherapy with chlorpromazine (n = 2133), haloperidol (n = 4454), quetiapine (n = 1513), and risperidone (n = 1046) between January 1, 2001, and December 31, 2011, were selected from a random sample of the 1 million enrollees of the Taiwan National Health Insurance Research Database. The association between antipsychotic prescription and mortality was estimated through Cox proportional hazard regression. To examine the mortality rates of antipsychotics at different exposure durations, we compared the differences among short-term (≤30 days), midterm (31-90 days), and long-term (>90 days) antipsychotic use. The mortality rates during the follow-up among the chlorpromazine, haloperidol, quetiapine, and risperidone groups were 17.4%, 45.5%, 26.8%, and 25.9%, respectively. The mortality risk among patients receiving haloperidol was the highest within 30 days of the prescription, after which the risk reduced rapidly. Compared with the patients receiving chlorpromazine, the mortality risk was higher in short-term (adjusted hazard ratio, 2.11; 95% confidence interval, 1.87-2.39) and midterm haloperidol users (1.86; 1.54-2.25) than in long-term users (0.99; 0.61-1.61). In conclusion, haloperidol use is associated with higher mortality risk than other antipsychotic medications. The mortality risk varies according to the duration of drug exposure. Underlying characteristics and medical conditions may influence the estimation of the mortality risk. Clinicians should pay attention to the mortality risk when prescribing antipsychotic medications, particularly for the elderly and critically ill patients.", "affiliations": "From the Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine; †Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; ‡Institute of Statistical Science, Academia Sinica; §Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica; ∥Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei; ¶Community Medicine Research Center, Chang-Gung Memorial Hospital, Keelung, Taiwan; #Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; and *Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.", "authors": "Wang\|Liang-Jen\|LJ\|;Lee\|Sheng-Yu\|SY\|;Yuan\|Shin-Sheng\|SS\|;Yang\|Kang-Chung\|KC\|;Yang\|Chun-Ju\|CJ\|;Lee\|Tung-Liang\|TL\|;Shyu\|Yu-Chiau\|YC\|", "chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D006220:Haloperidol; D018967:Risperidone; D002746:Chlorpromazine", "country": "United States", "delete": false, "doi": "10.1097/JCP.0000000000000451", "fulltext": null, "fulltext_license": null, "issn_linking": "0271-0749", "issue": "36(1)", "journal": "Journal of clinical psychopharmacology", "keywords": null, "medline_ta": "J Clin Psychopharmacol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D002746:Chlorpromazine; D016638:Critical Illness; D005260:Female; D005500:Follow-Up Studies; D006220:Haloperidol; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D016016:Proportional Hazards Models; D000069348:Quetiapine Fumarate; D012189:Retrospective Studies; D012307:Risk Factors; D018967:Risperidone; D013624:Taiwan; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "8109496", "other_id": null, "pages": "9-17", "pmc": null, "pmid": "26658260", "pubdate": "2016-02", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Risk of Mortality Among Patients Treated With Antipsychotic Medications: A Nationwide Population-Based Study in Taiwan.", "title_normalized": "risk of mortality among patients treated with antipsychotic medications a nationwide population based study in taiwan" }	[ { "companynumb": "TW-JNJFOC-20151224672", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "015923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WANG L, LEE S, YUAN S, YANG K, YANG C, LEE T, ET AL. RISK OF MORTALITY AMONG PATIENTS TREATED WITH ANTIPSYCHOTIC MEDICATIONS: A NATIONWIDE POPULATION-BASED STUDY IN TAIWAN. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 2016?36(1):9-17.", "literaturereference_normalized": "risk of mortality among patients treated with antipsychotic medications a nationwide population based study in taiwan", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20151231", "receivedate": "20151231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11883201, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]
{ "abstract": "Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky.\n\n\n\nWe describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits.\n\n\n\nThe evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.", "affiliations": "Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.", "authors": "Lehman\|Laura L\|LL\|;Bruccoleri\|Rebecca\|R\|;Danehy\|Amy\|A\|;Swanson\|Julie\|J\|;Mrakotsky\|Christine\|C\|;Smith\|Edward\|E\|;Orbach\|Darren B\|DB\|;Burstein\|Rami\|R\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0333102420950484", "fulltext": null, "fulltext_license": null, "issn_linking": "0333-1024", "issue": "41(1)", "journal": "Cephalalgia : an international journal of headache", "keywords": "CGRP receptor monoclonal antibody; Cerebral proliferative angiopathy; headache; migraine", "medline_ta": "Cephalalgia", "mesh_terms": null, "nlm_unique_id": "8200710", "other_id": null, "pages": "122-126", "pmc": null, "pmid": "32814432", "pubdate": "2021-01", "publication_types": "D016422:Letter", "references": null, "title": "Adverse effects of erenumab on cerebral proliferative angiopathy: A case report.", "title_normalized": "adverse effects of erenumab on cerebral proliferative angiopathy a case report" }	[ { "companynumb": "US-AMGEN-USASP2018086177", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYLENOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ERENUMAB-AOOE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "761077", "drugbatchnumb": "1093102", "drugcharacterization": "1", "drugcumulativedosagenumb": "70", "drugcumulativedosageunit": "003", "drugdosageform": "SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE", "drugdosagetext": "70 MG, QMO", "drugenddate": "20180617", "drugenddateformat": "102", "drugindication": "MIGRAINE", "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20180617", "drugstartdateformat": "102", "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AIMOVIG" } ], "patientagegroup": "5", "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83.1", "reaction": [ { "reactionmeddrapt": "Heart injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Encephalomalacia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebrovascular disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Amnesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ill-defined disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "DANEHY A. ADVERSE EFFECTS OF ERENUMAB ON CEREBRAL PROLIFERATIVE ANGIOPATHY: A CASE REPORT. CEPHALALGIA. 2021?41 (1):122?126", "literaturereference_normalized": "adverse effects of erenumab on cerebral proliferative angiopathy a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210508", "receivedate": "20180626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15070166, "safetyreportversion": 15, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210716" } ]
{ "abstract": "Spontaneous hypoglycemia is a puzzling clinical problem and an important reason for referral to endocrinologists. Several clinical conditions such as insulinomas, non-insulinoma pancreatogenous hypoglycemia syndrome, insulin autoimmune syndrome, postprandial hypoglycemia (reactive hypoglycemia), non-islet cell tumor hypoglycemia, primary adrenal insufficiency, hypopituitarism, and critical illness can be associated with spontaneous hypoglycemia. Rarely, in patients with mental health issues, factious hypoglycemia from extrinsic insulin use or ingestion of oral hypoglycemic agents can obfuscate the clinical picture for clinicians trying to identify an organic cause. In those presenting with Whipple's triad (symptoms ± signs of hypoglycemia, low plasma glucose, and resolution symptoms ± signs after hypoglycemia correction), a 72-h supervised fast test with measurement of plasma insulin, c-peptide, pro-insulin, and beta-hydroxybutyrate levels, coupled with plasma/urine sulphonylurea screen, forms the first step in diagnostic evaluation. A mixed meal test is preferable for those with predominantly postprandial symptoms. Additional non-invasive and/or invasive diagnostic evaluation is necessary if an organic hypoglycemic disorder is suspected. With the aid of a few brief clinical case scenarios, we discuss the diagnostic evaluation and management of spontaneous hypoglycemia through this comprehensive article.", "affiliations": "Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK.;Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK.;Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK. drpappachan@yahoo.co.in.", "authors": "Kandaswamy\|Leelavathy\|L\|;Raghavan\|Rajeev\|R\|;Pappachan\|Joseph M\|JM\|http://orcid.org/0000-0003-0886-5255", "chemical_list": "D001786:Blood Glucose; D007328:Insulin", "country": "United States", "delete": false, "doi": "10.1007/s12020-016-0902-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1355-008X", "issue": "53(1)", "journal": "Endocrine", "keywords": "72-Hour supervised fast test; Insulin autoimmune syndrome; Insulinoma; Non-insulinoma pancreatogenous hypoglycemia syndrome; Non-islet cell tumor hypoglycemia; Postprandial hypoglycemia (reactive hypoglycemia); Spontaneous hypoglycemia", "medline_ta": "Endocrine", "mesh_terms": "D000328:Adult; D001786:Blood Glucose; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007328:Insulin; D007340:Insulinoma; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D019518:Postprandial Period", "nlm_unique_id": "9434444", "other_id": null, "pages": "47-57", "pmc": null, "pmid": "26951054", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25922806;19440117;22188732;25918682;26001537;21470994;23671155;25915566;26760044;23249786;18931647;15767809;21245985;19129539;23074233;26566426;26577133;17127144;24641805;24645840;10190379;24765253;21134557;24423303;21366479;15754739;9356020;10999812;21306234;25002326;26508374;25737101;26312578;23979685;17856569;23636530;26315093;24921202;23430217;16670629;20628679;17609300;17611903;10500933;17609405;26107678;19141587;26050581;7716548;24275188;24622317;24599222;23425640;26704781;24459236;23669476;23082777;22261919;15880279;16253899;10500928;16860583;19088155", "title": "Spontaneous hypoglycemia: diagnostic evaluation and management.", "title_normalized": "spontaneous hypoglycemia diagnostic evaluation and management" }	[ { "companynumb": "GB-NOVOPROD-500150", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN HUMAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019991", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN INSULIN" } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemic unconsciousness", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEELAVATHY KANDASWAMY. SPONTANEOUS HYPOGLYCEMIA: DIAGNOSTIC EVALUATION AND MANAGEMENT. ENDOCRINE. 2016;53:47-57", "literaturereference_normalized": "spontaneous hypoglycemia diagnostic evaluation and management", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20160715", "receivedate": "20160715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12561482, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "To evaluate and compare the effectiveness and adverse effects of intramuscular (IM) olanzapine and IM aripiprazole for the treatment of agitated patients with schizophrenia in clinical practice.\n\n\n\nA 24-hour randomized double-blind study carried out at a psychiatric hospital in Thailand enrolled adult patients (18-65years old) with schizophrenia experiencing agitation. Patients received one dose of IM olanzapine or IM aripiprazole followed by routine oral psychotropic medications. Efficacy was primarily measured using the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC).\n\n\n\nA total of 80 patients with a PANSS-EC score range of 22-35 entered the study, of whom 13% had a medical comorbidity and 40% a history of active substance abuse. The 40 patients receiving IM olanzapine showed greater improvement than the 40 patients receiving IM aripiprazole in PANSS-EC scores at 2h after the injection (p=0.002) but not at 24h. The two treatments were well tolerated. Patients receiving IM olanzapine experienced greater somnolence than those receiving IM aripiprazole. There were no clinically relevant changes in vital signs in either group.\n\n\n\nThe results indicate that IM olanzapine and aripiprazole are similarly effective and well tolerated in the real-world treatment of agitation associated with schizophrenia over the first 24h. However, in the early hours, IM olanzapine may produce more sedation and reductions in agitation.", "affiliations": "Nakhon Sawan Rajanagarindra Psychiatric Hospital, Phayuhakhiri, Nakhon Sawan 60130, Thailand. Electronic address: kittipeerachon@outlook.com.;Nakhon Sawan Rajanagarindra Psychiatric Hospital, Phayuhakhiri, Nakhon Sawan 60130, Thailand. Electronic address: warawat@hotmail.co.th.", "authors": "Kittipeerachon\|Mantana\|M\|;Chaichan\|Warawat\|W\|", "chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000068180:Aripiprazole; D000077152:Olanzapine", "country": "Netherlands", "delete": false, "doi": "10.1016/j.schres.2016.07.017", "fulltext": null, "fulltext_license": null, "issn_linking": "0920-9964", "issue": "176(2-3)", "journal": "Schizophrenia research", "keywords": "Agitation; Aripiprazole; Intramuscular; Olanzapine; Schizophrenia", "medline_ta": "Schizophr Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001569:Benzodiazepines; D057186:Comparative Effectiveness Research; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011569:Psychiatric Status Rating Scales; D011595:Psychomotor Agitation; D012559:Schizophrenia; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8804207", "other_id": null, "pages": "231-238", "pmc": null, "pmid": "27461399", "pubdate": "2016-10", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D065007:Pragmatic Clinical Trial", "references": null, "title": "Intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia: A pragmatic double-blind randomized trial.", "title_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial" }	[ { "companynumb": "US-CIPLA LTD.-2016US19415", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombophlebitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231-238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "1", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865294, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19395", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861467, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19412", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONFUSIONAL STATE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861397, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19389", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZUCLOPENTHIXOL DECANOATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZUCLOPENTHIXOL DECANOATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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"drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPHA-ADRENOMIMETIC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOMEPROMAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOPROMAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORPROMAZINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CASTOR OIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASTOR OIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arteriosclerosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865297, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19408", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENICILLIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOXYMETHYLPENICILLIN BENZATHINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORPROMAZINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861448, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19384", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPENTIXOL DECANOATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPENTHIXOL DECANOATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asphyxia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865298, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19402", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, OVER 6 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19382", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861196, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19386", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861446, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19381", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMISULPRIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMISULPRIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FERROUS FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS FUMARATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10 MG, SINGLE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOTEPINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOTEPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic aneurysm rupture", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861129, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19392", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhagic stroke", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865299, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19411", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19420", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "203333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "203333", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOMOTOR HYPERACTIVITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombophlebitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH.. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856422, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19399", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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"summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861215, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19414", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG, UNK, OVER 36 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATED DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sudden cardiac death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231-238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "1", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19391", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861475, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19397", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DELUSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19422", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENZTROPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90294", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENZTROPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG, OVER 21 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPHENAZINE DECANOATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPHENAZINE DECANOATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arteriosclerosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856423, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19396", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MANIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYAMEMAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYAMEMAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOXAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOXAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLORAZEPATE DIPOTASSIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLORAZEPATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861453, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19409", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEPOT ZUCLOPENTHIXOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19416", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VITAMIN B" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN B" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, OVER 12 HRS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENTAL DISORDER DUE TO A GENERAL MEDICAL CONDITION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiopulmonary failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL.. SCHIZOPHRENIA RESEARCH.. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "This review focuses on the evidence for the efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with all stages of chronic kidney disease (CKD) and at all ages. It describes the improving height prognosis for our patients both with and without rhGH; explains the underlying hormonal abnormalities that provide the rationale for rhGH use in CKD and the endocrine changes that accompany treatment; and views on who warrants treatment, with what dose, and how long for.", "affiliations": "Gt Ormond St Hospital for Children NHS Foundation Trust, London, WC1N3JH, UK. lesley.rees@gosh.nhs.uk.", "authors": "Rees\|Lesley\|L\|", "chemical_list": "D011994:Recombinant Proteins; D019382:Human Growth Hormone; D013006:Growth Hormone", "country": "Germany", "delete": false, "doi": "10.1007/s00467-015-3179-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0931-041X", "issue": "31(9)", "journal": "Pediatric nephrology (Berlin, Germany)", "keywords": "Final height; Growth; Growth hormone", "medline_ta": "Pediatr Nephrol", "mesh_terms": "D001827:Body Height; D002648:Child; D006130:Growth Disorders; D013006:Growth Hormone; D019382:Human Growth Hormone; D006801:Humans; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic", "nlm_unique_id": "8708728", "other_id": null, "pages": "1421-35", "pmc": null, "pmid": "26369925", "pubdate": "2016-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": "21398350;15692833;22187956;15682317;19500600;10201017;18584215;19863876;21947116;10912546;22278170;8660044;25659076;12000468;20526632;1715501;9438660;9475286;19965538;22336787;11149116;10912542;7910322;8771007;3352160;8969731;25594438;2587121;15782308;23559676;16583244;8648920;12750982;24178977;3060022;15253735;11149115;12110034;24728472;2769495;20522533;24970873;8120705;7577409;22021715;19159957;16773402;22145447;3133989;10912545;10210991;9773791;23708760;19940493;2319402;2400222;9186890;3117236;9100565;10084780;12376812;9745864;23628375;10872186;24609826;16861941;18198222;3153055;12734746;20013293;2377395;12014516;10775075;9055918;15504147;7525628;1919888;23793884;11006368;7577408;22886280;23582048;24662177;23465957;8792393", "title": "Growth hormone therapy in children with CKD after more than two decades of practice.", "title_normalized": "growth hormone therapy in children with ckd after more than two decades of practice" }	[ { "companynumb": "GB-EMD SERONO-8045318", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589972, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "GB-EMD SERONO-8045319", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "GB-EMD SERONO-8045316", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589973, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "When skin abnormalities in patients extend over several dermatomes, disseminated herpes zoster should be suspected. This complication is most often seen in immunocompromised patients.\n\n\n\nAn 87-year-old patient came to the dermatology outpatient clinic with several vesicles scattered over her body. She was being treated with methotrexate for rheumatoid arthritis. Upon physical examination, we found groups of vesicles in the area of the maxillary nerve as well as several solitary vesicles scattered over her body. We made the diagnosis of 'disseminated herpes zoster'. PCR test of fluid from one of the vesicles found Varicella zoster virus. We treated the patient with intravenous acyclovir for 48 hours after which we treated her with oral acyclovir for another 8 days. We temporarily halted methotrexate. Outpatient follow-up found that the patient's skin abnormalities had diminished significantly.\n\n\n\nThe risk of disseminated herpes zoster depends on several factors. Use of immunosuppressants is often not the only contributing factor. Risk of disseminated herpes zoster in a patient who is being treated with methotrexate depends on age, comorbidities and co-medication of the patient.", "affiliations": "Franciscus Gasthuis en Vlietland,afd. Dermatologie, Rotterdam.;Franciscus Gasthuis en Vlietland,afd. Dermatologie, Rotterdam.;Franciscus Gasthuis en Vlietland,afd. Reumatologie, Rotterdam.", "authors": "Wanders\|Sarah L\|SL\|;Loots\|Miriam A M\|MAM\|;Baak\|Mieke\|M\|", "chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir; D008727:Methotrexate", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2162", "issue": "164()", "journal": "Nederlands tijdschrift voor geneeskunde", "keywords": null, "medline_ta": "Ned Tijdschr Geneeskd", "mesh_terms": "D000212:Acyclovir; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008727:Methotrexate; D012307:Risk Factors", "nlm_unique_id": "0400770", "other_id": null, "pages": null, "pmc": null, "pmid": "33201634", "pubdate": "2020-09-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Risk factors for disseminated herpes zoster.", "title_normalized": "risk factors for disseminated herpes zoster" }	[ { "companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-275566", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANDERS SL, LOOTS MAM, BAAK M. RISK FACTORS FOR DISSEMINATED HERPES ZOSTER. NED?TIJDSCHR?GENEESKD. 2020?164(39):A7", "literaturereference_normalized": "risk factors for disseminated herpes zoster", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210719", "receivedate": "20210115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18746097, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "NL-TEVA-2021-NL-1869514", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "058", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "77655", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3000 MILLIGRAM DAILY; THREE TIMES PER DAY BY MOUTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "HERPES ZOSTER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM DAILY; BY MOUTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBDURAL HAEMATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "EYE OINTMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "HERPES ZOSTER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR." } ], "patientagegroup": "6", "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Keratitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANDERS SL, LOOTS MAM, BAAK M. RISK FACTORS FOR DISSEMINATED HERPES ZOSTER. NED?TIJDSCHR?GENEESKD 2020?164(39):A7.", "literaturereference_normalized": "risk factors for disseminated herpes zoster", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210219", "receivedate": "20210121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18769755, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]
{ "abstract": "Concomitant use of anticoagulant and antiplatelet agents can increase the risk of gastrointestinal bleed (GIB). Use of proton pump inhibitors (PPIs) has been proposed to decrease the risk of GIB in patients on combined antithrombotic therapy (CAT).\n\n\n\nTo describe the current utilization of PPIs in veteran patients on CAT and associated clinical predictors of GIB.\n\n\n\nThis retrospective study included patients on CAT receiving PPIs, with at least one of the CAT agents initiated between January 1, 2018 and October 30, 2018. Data were extracted from the computerized patient record system. Primary end point included estimating proportion of patients on CAT receiving PPI co-therapy, describing patient characteristics, and identifying clinical predictors of GIB. Secondary outcomes included reporting GIB events and all-cause mortality. Additional outcome was to validate the five-factor risk score (FFRS) for GIB in patients on CAT and compare its overall predictive performance to HAS-BLED score.\n\n\n\nThis study reports an overall rate of PPI co-therapy in patients on CAT of 40.9% (484/1181), with only 22.3% of patients on CAT receiving PPI for GIB prophylaxis. There was no difference in the mean follow up duration of PPI users and PPI co-therapy (264.01 vs 271.92 days; p=0.3761). Current alcohol use (p=0.005), current smokers (p=0.022), chronic kidney disease (p=0.004), peptic ulcer disease (p<0.001), and non-steroidal anti-inflammatory drug use (p=0.048) were significant predictors of GIB in multivariate analyses of our study cohort. We further provide exploratory validation that use of a simplified FFRS to predict GIB showed a trend towards better overall predictive performance as compared to HAS-BLED score (C-statistic: 0.738; 95% CI 0.684-0.787 for FFRS vs C-statistic: 0.596; 95% CI 0.538-0.653 for HAS-BLED; p=0.0094).\n\n\n\nThis study reports lower rate of PPI co-therapy in veteran patients on CAT per currently available guidance. Further we explore utilization of simplified FFRS model to predict GIB in patients on CAT with long-term PPI co-therapy.", "affiliations": "Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.", "authors": "Patil\|Tanvi\|T\|0000-0001-7257-3463;Murphy\|Kimberly\|K\|;Woodard\|Laura\|L\|;Lebrecht\|Morgan\|M\|", "chemical_list": "D005343:Fibrinolytic Agents; D054328:Proton Pump Inhibitors", "country": "United States", "delete": false, "doi": "10.1002/phar.2477", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0008", "issue": "40(12)", "journal": "Pharmacotherapy", "keywords": "Anticoagulation; Antiplatelets; HAS-BLED; antithrombotic; bleeding risk scores; gastrointestinal bleed; proton pump inhibitor", "medline_ta": "Pharmacotherapy", "mesh_terms": "D000368:Aged; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D054328:Proton Pump Inhibitors; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D014728:Veterans", "nlm_unique_id": "8111305", "other_id": null, "pages": "1219-1227", "pmc": null, "pmid": "33073362", "pubdate": "2020-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Proton Pump Inhibitor Utilization in Veteran Patients on Combined Antithrombotic Therapy and Validation of Simplified Bleeding Risk Score.", "title_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score" }	[ { "companynumb": "US-TEVA-2021-US-1907209", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181444, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130380", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295448", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232724, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130383", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191524, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295470", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "85", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232454, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295495", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232704, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130352", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181207, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130375", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191377, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295434", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232727, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907214", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210097, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130371", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191967, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907190", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181447, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130391", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295431", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232017, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295459", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232437, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210098, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295477", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232438, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130363", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184658, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295494", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232448, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295469", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130389", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130354", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181268, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130370", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "85", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184728, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130362", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19196908, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907201", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210116, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130377", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295460", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232436, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130379", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210517", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191466, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130360", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184586, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295426", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232626, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295428", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE MAGNESIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200882", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295461", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232726, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295492", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295489", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295483", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210259, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295419", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200794", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232439, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130378", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130351", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": "6", "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181122, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295452", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907213", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210262, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130373", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186652, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130376", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19196612, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130384", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191522, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295497", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232702, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295450", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130359", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184590, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907188", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210726", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210260, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295417", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200794", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232440, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130387", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191650, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295465", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232720, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130369", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19197070, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295486", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232700, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295427", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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"drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232625, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130390", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PRASUGREL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRASUGREL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295424", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232015, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295500", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232775, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130388", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200425, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295421", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232435, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130358", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181541, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295472", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210261, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295453", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295462", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232721, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130366", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186653, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295464", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG,UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232783, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295481", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191973, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295498", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nMutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0-61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias.\n\n\nCONCLUSIONS\nVariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing \"ankyrin-B\" syndrome. (Circ J 2016; 80: 2435-2442).", "affiliations": "Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science.", "authors": "Ichikawa\|Mari\|M\|;Aiba\|Takeshi\|T\|;Ohno\|Seiko\|S\|;Shigemizu\|Daichi\|D\|;Ozawa\|Junichi\|J\|;Sonoda\|Keiko\|K\|;Fukuyama\|Megumi\|M\|;Itoh\|Hideki\|H\|;Miyamoto\|Yoshihiro\|Y\|;Tsunoda\|Tatsuhiko\|T\|;Makiyama\|Takeru\|T\|;Tanaka\|Toshihiro\|T\|;Shimizu\|Wataru\|W\|;Horie\|Minoru\|M\|", "chemical_list": "C498994:ANK2 protein, human; D017487:Ankyrins", "country": "Japan", "delete": false, "doi": "10.1253/circj.CJ-16-0486", "fulltext": null, "fulltext_license": null, "issn_linking": "1346-9843", "issue": "80(12)", "journal": "Circulation journal : official journal of the Japanese Circulation Society", "keywords": null, "medline_ta": "Circ J", "mesh_terms": "D000328:Adult; D017487:Ankyrins; D001145:Arrhythmias, Cardiac; D044466:Asians; D002648:Child; D005091:Exons; D005260:Female; D030342:Genetic Diseases, Inborn; D006801:Humans; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D013577:Syndrome", "nlm_unique_id": "101137683", "other_id": null, "pages": "2435-2442", "pmc": null, "pmid": "27784853", "pubdate": "2016-11-25", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes.", "title_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes" }	[ { "companynumb": "JP-PFIZER INC-2017002636", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE SODIUM" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "065230", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE SODIUM" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "065230", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLAZOLINE HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLAZOLINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Long QT syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA, M.. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRCULATION JOURNAL. 2016;80(12):2435-2442", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170512", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089294, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "JP-ACS-000498", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLAZOLINE HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLAZOLINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K ET AL. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. 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PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. 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PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRC J. 2016 DEC;80: 2435-42. DOI: 10.1253/CIRCJ.CJ-16-0486. ACCESSED: 2016 OCT 25.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170119", "receivedate": "20170119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13131947, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-BAUSCH-BL-2017-000224", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FAMOTIDINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "019462", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAMOTIDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETIZOLAM" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETIZOLAM" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Long QT syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRCULATION JOURNAL. 2016;80(12):2435-2442.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": null, "receiptdate": "20170109", "receivedate": "20170109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13099409, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-ROCHE-1875263", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "63239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "63239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLAZOLINE HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLAZOLINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Long QT syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K ET AL. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES.. CIRCULATION JOURNAL. 2016;80(12):2435-2442.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13090790, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "An elderly patient with multiple myeloma (MM) was being treated with several regimens and developed a severe drug eruption, necessitating the use of atovaquone instead of trimethoprim-sulfamethoxazole for pneumocystis pneumonia (PCP) prophylaxis. For progressive MM, treatment with isatuximab, an anti-CD38 monoclonal antibody, was started. During the treatment, he developed Listeria monocytogenes bacteremia and recovered quickly with ampicillin administration. CD38 is closely related to the innate immune response against L. monocytogenes, and isatuximab may increase the risk of infection. Therefore, trimethoprim-sulfamethoxazole may be useful in the prevention of not only PCP but also L. monocytogenes infection.", "affiliations": "Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.", "authors": "Ueno\|Toshiyuki\|T\|;Ohta\|Takanori\|T\|;Imanaga\|Hiroshi\|H\|;Nakazawa\|Megumi\|M\|;Sato\|Yoriko\|Y\|;Sugio\|Yasuhiro\|Y\|;Uchida\|Yujiro\|Y\|;Ohno\|Yuju\|Y\|;Uehara\|Yasufumi\|Y\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000599209:isatuximab", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.7509-21", "fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34024861\n10.2169/internalmedicine.7509-21\nCase Report\nListeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma\nUeno Toshiyuki 1\nOhta Takanori 1\nImanaga Hiroshi 2\nNakazawa Megumi 3\nSato Yoriko 3\nSugio Yasuhiro 1\nUchida Yujiro 3\nOhno Yuju 1\nUehara Yasufumi 1\n1 Department of Hematology, Kitakyushu Municipal Medical Center, Japan\n2 Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Japan\n3 Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan\nCorrespondence to Dr.　Toshiyuki Ueno, toshi.u.57@gmail.com\n\n22 5 2021\n15 11 2021\n60 22 36053608\n8 3 2021\n30 3 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nAn elderly patient with multiple myeloma (MM) was being treated with several regimens and developed a severe drug eruption, necessitating the use of atovaquone instead of trimethoprim-sulfamethoxazole for pneumocystis pneumonia (PCP) prophylaxis. For progressive MM, treatment with isatuximab, an anti-CD38 monoclonal antibody, was started. During the treatment, he developed Listeria monocytogenes bacteremia and recovered quickly with ampicillin administration. CD38 is closely related to the innate immune response against L. monocytogenes, and isatuximab may increase the risk of infection. Therefore, trimethoprim-sulfamethoxazole may be useful in the prevention of not only PCP but also L. monocytogenes infection.\n\nListeria monocytogenes\nCD38\nisatuximab\nmultiple myeloma\n==== Body\npmcIntroduction\n\nListeria monocytogenes is a Gram-positive bacterium that enters the human body orally through food, such as meat and dairy products. Although L. monocytogenes is rarely pathogenic to humans, it can cause listeriosis, leading to meningitis and bacteremia in pregnant women, infants, elderly individuals, and cancer patients, with a high mortality rate (1,2).\n\nInvasive listeriosis sometimes develops in patients with hematologic malignancies, especially in those who have undergone stem cell transplantation because of severe insufficiency of cell-mediated immunity (3). In recent years, new agents with different mechanisms of action have been developed for the treatment of various hematologic malignancies. These agents can cause complex changes in immunity.\n\nIsatuximab, a monoclonal antibody that binds a specific epitope on the human CD38 receptor, is highly effective against multiple myeloma (MM). CD38 is closely related to the regulation of innate immunity against L. monocytogenes infection (4). Therefore, the use of isatuximab may be associated with an increase in the rate of Listeria infections.\n\nWe herein report a patient with MM who developed L. monocytogenes bacteremia during isatuximab therapy.\n\nCase Report\n\nThe patient, a 68-year-old Japanese man, presented with initial complaints of back pain. He was diagnosed with IgG lambda-type, symptomatic MM and thereafter received treatment at our institution for three years. At the time of the diagnosis, the patient's serum IgG level was 6,458 mg/dL, while the levels of serum-free lambda and kappa light chains were 970 and 13.7 mg/L, respectively. Bone marrow aspiration showed hyperplastic bone marrow with 48% abnormal plasma cells. A chromosome test revealed deletion of the Y chromosome but no other high-risk chromosomal abnormalities. Based on the revised international staging system for MM, the case was categorized as stage III.\n\nThe patient was treated with bortezomib, lenalidomide, and dexamethasone (VRD) as first-line therapy. Trimethoprim-sulfamethoxazole (TMP-SMX) was also started at the beginning of the treatment to prevent pneumocystis pneumonia (PCP). After two cycles of VRD, the patient achieved a partial response and was subsequently treated with lenalidomide and dexamethasone (RD) therapy. During RD therapy, the patient developed a severe skin rash suspected of being drug eruption; treatment for MM was therefore discontinued, and corticosteroids were started. Since the drug-induced lymphocyte stimulation test (DLST) was positive for several drugs, including TMP-SMX, the suspected drugs were discontinued, and PCP prophylaxis was substituted with aerosolized pentamidine.\n\nThe patient's MM worsened with mass formation in the sternum and clavicle. Therefore, the patient was subjected to several treatment modalities to address the relapse. Carfilzomib, lenalidomide, and dexamethasone (KRD) therapy was first administered, followed by daratumumab, bortezomib, and dexamethasone (DVD) and then pomalidomide and dexamethasone (PD) therapy. Following that, ixazomib, lenalidomide, and dexamethasone (IRD) therapy was concurrently administered with radiation, which was followed by PD therapy. The patient was subsequently treated with elotuzumab, pomalidomide, and dexamethasone (EPD) therapy. However, despite receiving the above-mentioned treatments, his MM progressively worsened. Therefore, isatuximab, pomalidomide, and dexamethasone (Isa-PD) therapy was started. At this time, atovaquone was being used for PCP prophylaxis.\n\nThe Isa-PD schedule was planned with isatuximab 10 mg/kg on days 1, 8, 15, and 22; pomalidomide 2 mg (maximum tolerated dose) on days 1 to 21; and dexamethasone 40 mg on days 1, 8, 15, and 22. Atovaquone was used for PCP prophylaxis, and a small dose of a corticosteroid was continued to treat the drug eruption. On day 5 after the onset of Isa-PD therapy, the patient developed a high fever and hypotension and was administered cefepime under suspicion of febrile neutropenia (FN).\n\nThe laboratory test data collected at that time are summarized in Table. Blood culture samples were positive for a Gram-positive bacterium, which was confirmed to be L. monocytogenes. The isolate was found to be sensitive to ampicillin (minimum inhibitory concentration of 0.5 μg/mL). The patient had no gastrointestinal symptoms prior to the development of L. monocytogenes bacteremia and no symptoms or signs suggestive of meningitis or encephalitis. Treatment was then switched from cefepime to ampicillin for 14 days, and his symptoms resolved rapidly with ampicillin treatment. Furthermore, MM showed a good response despite the interruption of Isa-PD treatment after day 21. Whether or not TMP-SMX treatment was the main cause of the drug eruption was unclear, since the DLST was positive for several drugs, and the skin rash was clearly improved at the time. Therefore, TMP-SMX was resumed in small doses on a trial basis during the second cycle of Isa-PD therapy, and neither the skin rash nor L. monocytogenes bacteremia relapsed.\n\nTable. Laboratory Findings at the Onset of Bacteremia.\n\nComplete blood cell count\tBlood chemistry\t\t\t\t\nWhite blood cell\t10,200\t/µL\tTotal protein\t6.7\tg/dL\tBlood urea nitrogen\t49.8\tmg/dL\t\nNeutrophil\t94.9\t%\tAlbumin\t1.9\tg/dL\tCreatinine\t1.4\tmg/dL\t\nLymphocyte\t1.2\t%\tTotal bilirubin\t0.6\tmg/dL\tCreatine kinase\t14\tU/L\t\nMonocyte\t3.3\t%\tAspartate transaminase\t32\tU/L\tAmylase\t125\tU/L\t\nEosinophil\t0.2\t%\tAlanine aminotransferase\t35\tU/L\tUric acid\t6.4\tmg/dL\t\nBasophil\t0.4\t%\tLactate dehydrogenase\t128\tU/L\tC-reactive protein\t7.35\tmg/dL\t\nHemoglobin\t9.3\tg/dL\tAlkaline phosphatase\t222\tU/L\t\t\t\t\nPlatelet\t20.8×104\t/µL\tγ-Glutamyltransferase\t91\tU/L\t\t\t\t\n\nFigure shows the complete treatment regimen of the patient after MM was diagnosed.\n\nFigure. Clinical course of the patient. DVD: daratumumab, lenalidomide, and dexamethasone, EPD: elotuzumab, pomalidomide, and dexamethasone, IRD: ixazomib, lenalidomide, and dexamethasone, Isa-PD: isatuximab, pomalidomide, and dexamethasone, KRD: carfilzomib, lenalidomide, and dexamethasone, LM: Listeria monocytogenes, MM: multiple myeloma, PCP: pneumocystis pneumonia, PD: pomalidomide and dexamethasone, RD: lenalidomide and dexamethasone, TMP-SMX: trimethoprim-sulfamethoxazole, VRD: bortezomib, lenalidomide, and dexamethasone\n\nDiscussion\n\nL. monocytogenes is an intracellular parasitic bacterium that can survive and proliferate within macrophages. Cell-mediated immunity by immune cells, such as activated macrophages and dendritic cells, plays an important role in the innate immune response against L. monocytogenes (5). CD38 is expressed in activated macrophages and is essential for their regulation. It has been shown that CD38-knockout mice have increased susceptibility to L. monocytogenes infection due to the inhibition of macrophage migration to the infection site (4). This may also be observed in humans, since CD38 is also induced in human macrophages upon infection (6). Therefore, monoclonal antibodies, such as daratumumab, which targets CD38, also highly expressed in myeloma cells, may increase the risk of L. monocytogenes infection. In a nested case-control study conducted on patients amid an outbreak at a commercial eatery, patients who received daratumumab were at a 340-fold higher risk of developing L. monocytogenes infection than other cancer patients. In addition, patients treated with daratumumab had a 75-fold higher risk of listeriosis than all other MM patients, although the study included high-risk patients who underwent stem cell transplantation and received experimental therapies for relapsed refractory disease (7). In fact, there have been two case reports of L. monocytogenes infections after the administration of daratumumab (8,9). Isatuximab is a human anti-CD38 monoclonal antibody similar to daratumumab; however, the antibody targets different amino acid sequences and possesses strong proapoptotic activity independent of cross-linking agents (10). As demonstrated in this case, isatuximab may be a risk factor for the development of L. monocytogenes infection, similar to daratumumab.\n\nThe other risk factors that may lead to L. monocytogenes infection include pregnancy, organ transplant, tumor necrosis factor antagonists, cancer chemotherapy, old age, diabetes, and high-dose steroids (1,2). Therefore, the L. monocytogenes infection in our patient may not have been due to isatuximab alone but rather to multiple factors, such as MM therapy, old age, and long-term use of corticosteroids. However, throughout the course of treatment in this case, which included daratumumab therapy as well, L. monocytogenes infection did not develop. The infection first developed after the administration of isatuximab, suggesting that isatuximab was an important factor in the establishment of the infection.\n\nRoutine stool culture is not recommended for L. monocytogenes detection, as asymptomatic fecal carriage complicates the prediction of the risk of infection (2). This difficulty in reliably predicting conditions that cause L. monocytogenes infection can result in severe infections in patients with hematologic malignancies when the bacterium becomes pathogenic (3). Therefore, prevention and early treatment of L. monocytogenes infection are important. The primary way of preventing L. monocytogenes infection is to avoid consuming contaminated foods, such as dairy products and meat. Second, TMP-SMX, which has been reported as an independent protective factor against L. monocytogenes infection, should be used prophylactically as part of the treatment regimen (11). L. monocytogenes meningoencephalitis and cerebral abscesses have been reported after switching from TMP-SMX to atovaquone for preventing PCP (12). In the present case, L. monocytogenes bacteremia developed after TMP-SMX treatment was switched to atovaquone and did not recur after the administration of TMP-SMX was re-started, suggesting the effectiveness of TMP-SMX in preventing the infection. Ampicillin is the first treatment of choice for L. monocytogenes infection; other therapeutic options include TMP-SMX and meropenem, whereas cephem antibiotics are usually ineffective (2,3). Fourth-generation cephem drugs, which are commonly used in the management of FN, may be inadequate for the initial treatment of L. monocytogenes infection. Therefore, meropenem, which is effective against both listeriosis and FN, should be considered, especially after the use of anti-CD38 antibodies.\n\nIn conclusion, we described a patient with MM who developed L. monocytogenes bacteremia during isatuximab therapy. Isatuximab can cause L. monocytogenes infection and may necessitate prophylaxis with TMP-SMX and dietary guidance.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWe would like to thank the nursing staff who cared for the patient at Kitakyushu Municipal Medical Center and the technical staff at the hospital's bacteriology laboratory.\n==== Refs\n1. Vázquez-Boland JA , Kuhn M , Berche P , et al . Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 14 : 584-640, 2001.11432815\n2. Shoham S , Bartlett JG . Listeria monocytogenes. Johns Hopkins Medicine POC-IT guides [Internet]. [cited 2021 Feb 27]. Available from: https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540318/all/Listeia_monocytogenes\n3. Rivero GA , Torres HA , Rolston KVI , Kontoyiannis DP . Listeria monocytogenes infection in patients with cancer. Diagn Microbiol Infect Dis 47 : 393-398, 2003.14522512\n4. Lischke T , Heesch K , Schumacher V , et al . CD38 controls the innate immune response against Listeria monocytogenes. Infect Immun 81 : 4091-4099, 2013.23980105\n5. Maudet C , Levallois S , Disson O , Lecuit M . Innate immune responses to Listeria in vivo. Curr Opin Microbiol 59 : 95-101, 2021.33307408\n6. Amici SA , Young NA , Narvaez-Miranda J , et al . CD38 is robustly induced in human macrophages and monocytes in inflammatory conditions. Front Immunol 9 : 1593, 2018.30042766\n7. Khan S , Vaisman A , Hota SS , et al . Listeria susceptibility in patients with multiple myeloma receiving daratumumab-based therapy. JAMA Oncol 6 : 293-294, 2020.31774462\n8. Hung DLL , Lau SKP , Woo PCY . Severe sepsis caused by Listeria monocytogenes in a patient given monoclonal antibodies against CD38 and proteosome inhibitor. Infect Microbes Dis 1 : 30-31, 2019.\n9. Horikita F , Hashiguchi J , Nagashima T . Post colonoscopic Listeria monocytogenes meningitis in a patient with multiple myeloma during daratumumab-based therapy. Rinsho Ketsueki (Jpn J Clin Hematol) 61 : 1611-1615, 2020 (in Japanese, Abstract in English).\n10. Deckert J , Wetzel MC , Bartle LM , et al . SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res 20 : 4574-4583, 2014.24987056\n11. Fernàndez-Sabé N , Cervera C , López-Medrano F , et al . Risk factors, clinical features, and outcomes of listeriosis in solid-organ transplant recipients: a matched case-control study. Clin Infect Dis 49 : 1153-1159, 2009.19751149\n12. Adjei PC . 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"medicinalproduct": "POMALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATOVAQUONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATOVAQUONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Ueno T, Ohta T, Imanaga H, Nakazawa M, Sato Y, Sugio Y et al.. Listeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma.. Internal medicine (Tokyo, Japan). 2021", "literaturereference_normalized": "listeria monocytogenes bacteremia during isatuximab therapy in a patient with multiple myeloma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220329", "receivedate": "20220329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20647802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-301884", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "1", 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Therapeutic product effect incomplete", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, OHTA T, IMANAGA H, NAKAZAWA M, SATO Y, SUGIO Y, ET AL. LISTERIA MONOCYTOGENES BACTEREMIA DURING ISATUXIMAB THERAPY IN A PATIENT WITH MULTIPLE MYELOMA. INTERN MED. 2021?NO VOLUME:NO PAGINATION", "literaturereference_normalized": "listeria monocytogenes bacteremia during isatuximab therapy in a patient with multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210628", "receivedate": "20210628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19468075, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "OBJECTIVE\nReports of manic episodes associated with the use of cholinesterase inhibitors (including donepezil) are limited. Despite the previous notion of procholinergic drugs potentially inducing depression, the contemporary evidence for cholinesterase inhibitors appears to also indicate a trend for elevated mood (in patients with or without a history of depressive disorder).\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nThe authors report a case of a manic episode with psychotic features associated with the up-titration of donepezil in a patient with Alzheimer's disease and a distant history of major depression but without a preexisting bipolar disorder.\n\n\nCONCLUSIONS\nPathophysiology of donepezil-induced mania appears to contradict the traditional cholinergic-adrenergic hypothesis. Donepezil-associated mania should be suspected after donepezil initiation/dose up-titration when correlated to new onset of mania. Donepezil should be used more cautiously in patients with current or previous mood episodes or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Although this requires further investigation in different patient populations, there may be subtypes of older patients with neurocognitive disorders who are particularly vulnerable to activation effects of cholinesterase inhibitors.", "affiliations": "Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. Electronic address: ahategan@stjosham.on.ca.;Department of Psychiatry/Langley Porter Psychiatric Institute, Consultation/Liaison Service, University of California San Francisco Medical Center, San Francisco, CA, USA.", "authors": "Hategan\|Ana\|A\|;Bourgeois\|James A\|JA\|", "chemical_list": "D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0163-8343", "issue": "38()", "journal": "General hospital psychiatry", "keywords": "Cholinesterase inhibitors; Dementia; Donepezil; Mania; Neurocognitive disorders", "medline_ta": "Gen Hosp Psychiatry", "mesh_terms": "D000341:Affective Disorders, Psychotic; D000368:Aged; D000544:Alzheimer Disease; D001714:Bipolar Disorder; D003865:Depressive Disorder, Major; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines", "nlm_unique_id": "7905527", "other_id": null, "pages": "115.e1-4", "pmc": null, "pmid": "26598289", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Donepezil-associated manic episode with psychotic features: a case report and review of the literature.", "title_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature" }	[ { "companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-00154", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypomania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS J, RAO V. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN - HOSP - PSYCHIATRY 2016?38115 E1-115E4. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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"CYMBALTA" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Hategan A, Bourgeois JA.. Donepezil-associated manic episode with psychotic features: A case report and review of the literature. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160125", "receivedate": "20160125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11944631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-00153", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypomania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS J, BENAZZI F, ROSSI E. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160209", "receivedate": "20160209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12047471, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-00121", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS J. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160209", "receivedate": "20160209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12047481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-APOTEX-2016AP005930", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078841", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-DONEPEZIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078841", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COGNITIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-DONEPEZIL" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA.. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE.. GEN-HOSP-PSYCHIATRY. 2016?38:115E1-115E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160127", "receivedate": "20160127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11965671, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-PRINSTON PHARMACEUTICAL INC.-2016PRN00017", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, 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null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersexuality", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Jealous delusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Delusion of grandeur", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN HOSP PSYCHIATRY (DOI: 10.1016/J.GENHOSPPSYCH.2015.09.004). 2016?38:115E1-115E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160203", "receivedate": "20160203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11997461, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-MYLANLABS-2016M1002901", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090521", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090521", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG DAILY AND THEN INCREASED TO 10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COGNITIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN-HOSP-PSYCHIATRY 2016?38:115E1-115E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160125", "receivedate": "20160125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11948423, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" } ]
{ "abstract": "A 60-year-old woman with chronic renal failure due to a polycystic kidney underwent living kidney transplantation. Initial immunosuppressive therapy consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), prednisolone, and basiliximab. Furthermore, rituximab was administered, and double filtration plasmapheresis and plasma exchange were utilized because of ABO-incompatible transplantation, while intravenous immune serum globulin (IVIG) was given because donor specific antibody was positive. Four days after the renal transplantation, the patient developed visual abnormalities, a headache, and paralysis. Then, he became unconscious. Magnetic resonance imaging of the brain demonstrated bilateral posterior vasogenic edema. Our diagnosis was posterior reversible encephalopathy syndrome due to TAC neurotoxicity. After converting TAC to reduced cyclosporine and everolimus, the symptoms rapidly disappeared.", "affiliations": "The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.", "authors": "Ueda\|Norichika\|N\|;Kawamura\|Masataka\|M\|;Nakazawa\|Shigeaki\|S\|;Hirai\|Toshiaki\|T\|;Kishikawa\|Hidefumi\|H\|;Nishimura\|Kenji\|K\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "60(8)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D019520:Living Donors; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0421145", "other_id": null, "pages": "387-92", "pmc": null, "pmid": "25179989", "pubdate": "2014-08", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Posterior reversible encephalopathy syndrome (PRES) after kidney transplantation: a case report.", "title_normalized": "posterior reversible encephalopathy syndrome pres after kidney transplantation a case report" }	[ { "companynumb": "JP-BAXTER-2014BAX065333", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103133", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HLA MARKER STUDY POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMAGARD" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103133", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMAGARD" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA N, KAWAMURA M, NAKAZAWA S, HIRAI T, KISHIKAWA H, NISHIMURA K. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES) AFTER KIDNEY TRANSPLANTATION: A CASE REPORT. HINYOKIKA KIYO.ACTA UROLOGICA JAPONICA. 2014 JAN 01;60(8):387-392.", "literaturereference_normalized": "posterior reversible encephalopathy syndrome pres after kidney transplantation a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141111", "receivedate": "20141105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10566960, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]
{ "abstract": "A case of serial killing by poisoning by a 59-year-old practical nurse is discussed. Following a report by an emergency-room doctor of an attempted murder, police performed an investigation into all deaths of patients in the nurse's care. Earlier, a medico-legal cause-of-death investigation had been performed on two of these cadavers, but in the other three cases the death certificate had been issued after a medical investigation only. In two of these latter cases, the body had been cremated, but fixed histological samples taken at medical autopsy were available, while in one case the person had died recently and the body was thereafter exhumed and autopsied. All of the suspected victims were older people who required nursing, and the nurse's course of action was consistent in all cases. In the absence of ordinary post-mortem toxicology samples in the medical cases, extraordinary evidence--paraffin-embedded liver tissue samples originally taken for histology at autopsy--was successfully recovered in two cases and analyzed for drugs. In all five cases, drugs not prescribed to the patient were detected, including digoxin, dixyrazine, citalopram, venlafaxine, and benzodiazepines (diazepam, chlordiazepoxide, temazepam, and oxazepam). The nurse was eventually found guilty of five murders by poisoning, five attempted murders, and three aggravated assaults. The nurse was sentenced to life imprisonment.", "affiliations": "Hjelt Institute, Department of Forensic Medicine, University of Helsinki, Finland.", "authors": "Vuori\|Erkki\|E\|;Pelander\|Anna\|A\|;Rasanen\|Ilpo\|I\|;Juote\|Mikko\|M\|;Ojanperä\|Ilkka\|I\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/dta.1480", "fulltext": null, "fulltext_license": null, "issn_linking": "1942-7603", "issue": "5(9-10)", "journal": "Drug testing and analysis", "keywords": "drug; exhumation; homicide; paraffin-embedded tissue; poisoning; serial killer", "medline_ta": "Drug Test Anal", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D049249:Exhumation; D005260:Female; D005554:Forensic Medicine; D006708:Homicide; D006801:Humans; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D011041:Poisoning", "nlm_unique_id": "101483449", "other_id": null, "pages": "725-9", "pmc": null, "pmid": "23613335", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": null, "title": "A rare case of serial killing by poisoning.", "title_normalized": "a rare case of serial killing by poisoning" }	[ { "companynumb": "FI-FRI-1000044892", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NORDAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DESMETHYLDIAZEPAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020822", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM HYDROBROMIDE UNK" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20061119" } }, "primarysource": { "literaturereference": "VUORI E, PELANDER A, RASANEN I, JUOTE M, OJANPERA I. A RARE CASE OF SERIAL KILLING BY POISONING. DRUG TESTING AND ANALYSIS. 2013?725?729", "literaturereference_normalized": "a rare case of serial killing by poisoning", "qualification": "1", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20210813", "receivedate": "20130503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9270642, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Smoke inhalation is the most common cause of acute cyanide poisoning in the developed world. Hydroxocobalamin is an antidote for cyanide poisoning. There is little published about human intraosseous antidote administration. We present a case of intraosseous hydroxocobalamin administration in an adult smoke inhalation victim, found in cardiac arrest inside her burning manufactured home. Return of spontaneous circulation was achieved after 20 min of cardiopulmonary resuscitation. Five grams of hydroxocobalamin were subsequently given intraosseously. On hospital arrival, patient was found to have a respiratory-metabolic acidosis. She had red-coloured urine without haematuria, a known sequela of hydroxocobalamin administration. Patient's neurological status deteriorated, and she died 4 days after admission. This case highlights that intraosseously administered hydroxocobalamin seems to adequately flow into the marrow cavity and enter the circulatory system despite the non-compressible glass antidote vial. This appears to be only the second reported human case of intraosseous hydroxocobalamin administration.", "affiliations": "Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA Joshua.Mastenbrook@med.wmich.edu.;Department of Student Affairs, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.", "authors": "Mastenbrook\|Joshua\|J\|http://orcid.org/0000-0002-9928-3674;Zamihovsky\|Rachel\|R\|;Brunken\|Nathan\|N\|;Olsen\|Thomas\|T\|", "chemical_list": "D000931:Antidotes; D003486:Cyanides; D006879:Hydroxocobalamin", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-239523", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(3)", "journal": "BMJ case reports", "keywords": "emergency medicine; poisoning; prehospital; resuscitation; toxicology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000931:Antidotes; D003486:Cyanides; D005260:Female; D005390:Fires; D006323:Heart Arrest; D006801:Humans; D006879:Hydroxocobalamin; D015208:Smoke Inhalation Injury", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33692053", "pubdate": "2021-03-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest.", "title_normalized": "intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest" }	[ { "companynumb": "US-SERB S.A.S.-2123932", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXOCOBALAMIN" }, "drugadditional": null, "drugadministrationroute": "028", "drugauthorizationnumb": "022041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Gas poisoning", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYANOKIT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chromaturia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Mastenbrook J, Zamihovsky R, Brunken N, Olsen T. Intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest. BMJ Case Rep. 2021 Mar 10;14(3):e239523. doi: 10.1136/bcr-2020-239523.", "literaturereference_normalized": "intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20220114", "receivedate": "20220114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20335455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220423" } ]
{ "abstract": "Pancreatic cancer patients have a poor prognosis because of a low rate of resection that results from distant metastases or local advancement. We report a successful case of unresectable locally advanced pancreatic cancer in a patient who was curatively resected after combination therapy with nab-paclitaxel (nab-PTX) and gemcitabine (GEM). A 61-year-old man was referred for treatment of a 45-mm pancreatic tail tumor involving the celiac axis, common hepatic artery, and splenic artery that appeared as an abnormal soft-density mass on imaging. This patient's tumor was defined as unresectable due to local advancement, and, therefore, the powerful combined chemotherapy regimen of nab-PTX with GEM was initiated to allow for possible resection later. After three cycles of chemotherapy, a CT scan revealed that the soft-density mass around the celiac axis and common hepatic artery had dramatically disappeared, and the tumor was then determined to be a resectable lesion. Thus, distal pancreatectomy with en bloc celiac axis resection was performed and curability was achieved. There has been no tumor recurrence or distant metastasis at more than 12 months after surgery, and the patient remains alive at 17 months after initial chemotherapy.", "affiliations": "Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. mhiyoshi@med.miyazaki-u.ac.jp.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.", "authors": "Hiyoshi\|Masahide\|M\|http://orcid.org/0000-0002-2392-7787;Nanashima\|Atsushi\|A\|;Wada\|Takashi\|T\|;Tsuchimochi\|Yuki\|Y\|;Hamada\|Takeomi\|T\|;Yano\|Koichi\|K\|;Imamura\|Naoya\|N\|;Fujii\|Yoshiro\|Y\|", "chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel", "country": "Japan", "delete": false, "doi": "10.1007/s12328-017-0793-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1865-7265", "issue": "10(6)", "journal": "Clinical journal of gastroenterology", "keywords": "Conversion surgery; Curative resection; Gemcitabine; Locally advanced pancreatic cancer; Nab-paclitaxel", "medline_ta": "Clin J Gastroenterol", "mesh_terms": "D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D002445:Celiac Artery; D003841:Deoxycytidine; D006499:Hepatic Artery; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D017239:Paclitaxel; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D013157:Splenic Artery", "nlm_unique_id": "101477246", "other_id": null, "pages": "551-557", "pmc": null, "pmid": "29086227", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28040257;23907428;26842789;23913634;28736643;25547205;24131140;20134315;11100373;28179342;23660962;28101795;28588798;21620466;27841795;19097774;25258022;17592290;26136371;27304847;28177521;26655559;26350368;25408659;28373919;17981197;1359851;22642850;27022826", "title": "A successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab-paclitaxel with gemcitabine.", "title_normalized": "a successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab paclitaxel with gemcitabine" }	[ { "companynumb": "JP-PFIZER INC-2017512053", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80% DECREASED DOSE WAS ADMINISTERED ON DAY 15 IN THE SECOND AND THIRD CYCLES, (ON DAY 15)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80% DECREASED DOSE WAS ADMINISTERED ON DAY 15 IN THE SECOND AND THIRD CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAYS 1, 8, AND 15 EVERY 4 WEEKS FOR 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAYS 1, 8, AND 15 EVERY 4 WEEKS FOR 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIYOSHI, M.. A SUCCESSFUL CASE OF LOCALLY ADVANCED PANCREATIC CANCER UNDERGOING CURATIVE DISTAL PANCREATECTOMY WITH EN BLOC CELIAC AXIS RESECTION AFTER COMBINATION CHEMOTHERAPY OF NAB-PACLITAXEL WITH GEMCITABINE. CLINICAL JOURNAL OF GASTROENTEROLOGY. 2017?10 (6):551-557", "literaturereference_normalized": "a successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab paclitaxel with gemcitabine", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181012", "receivedate": "20171205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14251839, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]
{ "abstract": "Ophthalmic involvement appears rarely in multiple myeloma (MM). Ophthalmic findings are mostly noted as complications caused by disease or treatment. MM-associated with 6th nerve paralysis is a rare entity. Bortezomib, one of the novel agents used to treat MM, has neurotoxic effect and may cause permanent nerve damage. Herein, we report a 50-year-old male patient with MM who developed the 6th nerve paralysis while receiving bortezomib and discuss its relevant causes.", "affiliations": "Division of Haematology, Faculty of Medicine, Bezmialem Vakif University, Vatan Caddesi, Fatih, 34093 Istanbul, Turkey.;Istanbul Training and Research Hospital, Haematology Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Faculty of Medicine, Neurology Clinic, Bezmialem Vakif University, Fatih, Istanbul, Turkey.", "authors": "Cetin\|Guven\|G\|;Cem Ar\|M\|M\|;Cerit\|Abdullah\|A\|;Gozubenli\|Kubra\|K\|;Erdem\|Simge\|S\|;Halac\|Gulistan\|G\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1007/s12288-013-0252-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0971-4502", "issue": "30(Suppl 1)", "journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion", "keywords": "Bortezomib; Multiple myeloma; The 6th nerve paralysis", "medline_ta": "Indian J Hematol Blood Transfus", "mesh_terms": null, "nlm_unique_id": "9425818", "other_id": null, "pages": "70-2", "pmc": null, "pmid": "25332540", "pubdate": "2014-09", "publication_types": "D002363:Case Reports", "references": "15627827;19794956;20977708;11306489;18574024;11130748;12393500", "title": "A rare entity in multiple myeloma: six nerve paralysis.", "title_normalized": "a rare entity in multiple myeloma six nerve paralysis" }	[ { "companynumb": "TR-TAKEDA-2014MPI002840", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021602", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "VIth nerve paralysis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CETIN G, CEM AM, CERIT A, GOZUBENLI K, ERDEM S, HALAC G.. A RARE ENTITY IN MULTIPLE MYELOMA: SIX NERVE PARALYSIS.. INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION. 2014?30 (SUPPL 1):70-72", "literaturereference_normalized": "a rare entity in multiple myeloma six nerve paralysis", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190311", "receivedate": "20190311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16057848, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "Fixed drug eruption (FDE) is an uncommon medication-induced cutaneous reaction. A case of fluconazole-induced FDE is described. A 64-year-old woman presented with eight ovoid hyperpigmented patches on the arms, palm and lower leg that had recurred multiple times at the identical sites at seemingly random intervals over the prior six months. The clinicopathologic diagnosis strongly favored FDE, though the culprit medication remained elusive. Further evaluation and oral rechallenge confirmed the diagnosis of FDE to fluconazole. The patient had not related the eruption to this medication due to the short courses of therapy and prior use without incident. FDE to fluconazole has only been rarely reported in the literature. The presentation and evaluation of FDE is reviewed.", "affiliations": "University of Iowa, Department of Dermatology, Iowa City, IA, USA. hobartwalling@yahoo.com", "authors": "Walling\|Hobart W\|HW\|;Swick\|Brian L\|BL\|", "chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1545-9616", "issue": "9(8)", "journal": "Journal of drugs in dermatology : JDD", "keywords": null, "medline_ta": "J Drugs Dermatol", "mesh_terms": "D000284:Administration, Oral; D000935:Antifungal Agents; D003875:Drug Eruptions; D005260:Female; D015725:Fluconazole; D006801:Humans; D008875:Middle Aged", "nlm_unique_id": "101160020", "other_id": null, "pages": "1025-8", "pmc": null, "pmid": "20684158", "pubdate": "2010-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cutaneous fixed drug eruption to fluconazole.", "title_normalized": "cutaneous fixed drug eruption to fluconazole" }	[ { "companynumb": "US-DRREDDYS-USA/USA/16/0080119", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076658", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TINEA VERSICOLOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fixed drug eruption", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI O, HSU S. CUTANEOUS FIXED DRUG ERUPTION TO FLUCONAZOLE. DERMATOL ONLINE J. 2016;22(4):.", "literaturereference_normalized": "cutaneous fixed drug eruption to fluconazole", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12770266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]
{ "abstract": "OBJECTIVE\nThe current standard treatment for IgA nephropathy relies on steroid and/or immunosuppressive therapy and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB). This study examines the benefits and safety of combining valsartan with clopidogrel and leflunomide as a treatment for progressive IgA nephropathy.\n\n\nMETHODS\nPatients with primary IgA nephropathy, confirmed by renal biopsy, were recruited for this study. Patients were separated into four groups (n = 42 each) after 2 months of run-in period of valsartan treatment. All patients were treated with valsartan alone (Group 1) or valsartan and either clopidogrel (Group 2) or leflunomide (Group 3) or both clopidogrel and leflunomide (Group 4). Each group was followed up for their next 24 months for 24 h urinary protein excretion, serum creatinine and estimated glomerular filtration rate (eGFR) to assess the effect of the treatment. Adverse effects were recorded concurrently to evaluate the safety of the treatment.\n\n\nRESULTS\nOf all 168 patients, 107 were males and 61 were females, with an average age of 33.8 ± 8.79 years. Baseline characteristics were comparable among the four groups (P > 0.05) prior to the experimental treatment. There was a significant (P < 0.05) decrease in 24 h urinary protein excretion after 4 months of experimental treatment. At the end of the 24 months, groups 3 and 4 showed a respective 62.35% and 69.47% reduction in proteinuria. The serum creatinine was significantly higher (P < 0.05) in group 1 and 2 at the end of the follow-up, and their respective eGFR was significantly lower. The incidence of cardiovascular complication was 11.9% and 9.5% for group 1 and 3, respectively.\n\n\nCONCLUSIONS\nThe treatment with Valsartan combined with Clopidogrel and Leflunomide can reduce the urinary proteins loss and renal function deterioration for IgA nephropathy patients and cause minimal adverse reactions. Our study suggests a new clinical treatment option for IgA nephropathy.", "affiliations": "Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.", "authors": "Cheng\|Genyang\|G\|;Liu\|Dongwei\|D\|;Margetts\|Peter\|P\|;Liu\|Limin\|L\|;Zhao\|Zhanzheng\|Z\|;Liu\|Zhangsuo\|Z\|;Tang\|Lin\|L\|;Fang\|Yudong\|Y\|;Li\|Haijian\|H\|;Guo\|Yuanyuan\|Y\|;Chen\|Fengmei\|F\|;Liu\|Fengxun\|F\|", "chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000068756:Valsartan; D000077144:Clopidogrel; D003404:Creatinine; D000077339:Leflunomide; D014633:Valine; D013988:Ticlopidine", "country": "Australia", "delete": false, "doi": "10.1111/nep.12359", "fulltext": null, "fulltext_license": null, "issn_linking": "1320-5358", "issue": "20(2)", "journal": "Nephrology (Carlton, Vic.)", "keywords": "IgA nephropathy; clopidogrel; leflunomide; valsartan", "medline_ta": "Nephrology (Carlton)", "mesh_terms": "D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D002681:China; D000077144:Clopidogrel; D003404:Creatinine; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D006801:Humans; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D007668:Kidney; D000077339:Leflunomide; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011507:Proteinuria; D013777:Tetrazoles; D013988:Ticlopidine; D013997:Time Factors; D016896:Treatment Outcome; D014633:Valine; D000068756:Valsartan", "nlm_unique_id": "9615568", "other_id": null, "pages": "77-84", "pmc": null, "pmid": "25358874", "pubdate": "2015-02", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin A nephropathy.", "title_normalized": "valsartan combined with clopidogrel and or leflunomide for the treatment of progressive immunoglobulin a nephropathy" }	[ { "companynumb": "CN-SA-2015SA019768", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLACEBO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALSARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020839", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG G, LIU D, MARGETTS P, LIU L, ZHAO Z, LIU Z, ET AL. VALSARTAN COMBINED WITH CLOPIDOGREL AND/OR LEFLUNOMIDE FOR THE TREATMENT OF PROGRESSIVE IMMUNOGLOBULIN A NEPHROPATHY. NEPHROLOGY 2015;20(2):77-84. DOI:10.1111/NEP.12359", "literaturereference_normalized": "valsartan combined with clopidogrel and or leflunomide for the treatment of progressive immunoglobulin a nephropathy", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20150220", "receivedate": "20150220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10842280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "Continuous levodopa-carbidopa intestinal gel (LCIG) diminishes daily \"off\" time and dyskinesia in patients with advanced Parkinson's disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J).\n\n\n\nTo report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital.\n\n\n\nLevodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed.\n\n\n\nSixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose (LEDD) had increased by 30% compared to pre-LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died.\n\n\n\nMost patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.", "affiliations": "Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.;HUS Medical Imaging Center Helsinki University Helsinki Finland.;Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.", "authors": "Udd\|Marianne\|M\|0000-0001-8916-640X;Lyytinen\|Jukka\|J\|;Eerola-Rautio\|Johanna\|J\|;Kenttämies\|Anu\|A\|;Lindström\|Outi\|O\|;Kylänpää\|Leena\|L\|;Pekkonen\|Eero\|E\|", "chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa", "country": "United States", "delete": false, "doi": "10.1002/brb3.737", "fulltext": "\n==== Front\nBrain BehavBrain Behav10.1002/(ISSN)2157-9032BRB3Brain and Behavior2162-3279John Wiley and Sons Inc. Hoboken 10.1002/brb3.737BRB3737Original ResearchOriginal ResearchProblems related to levodopa‐carbidopa intestinal gel treatment in advanced Parkinson's disease Udd Marianne http://orcid.org/0000-0001-8916-640Xmarianne.udd@hus.fi \n1\nLyytinen Jukka \n2\n\n3\nEerola‐Rautio Johanna \n2\n\n3\nKenttämies Anu \n4\nLindström Outi \n1\nKylänpää Leena \n1\nPekkonen Eero \n2\n\n3\n\n1 \nDepartment of Surgery\nUnit of Therapeutic Endoscopy\nHelsinki University\nHelsinki\nFinland\n\n2 \nClinical Neurosciences, Neurology\nHelsinki University\nHelsinki\nFinland\n\n3 \nDepartment of Neurology\nHelsinki University Hospital and Helsinki University\nHelsinki\nFinland\n\n4 \nHUS Medical Imaging Center\nHelsinki University\nHelsinki\nFinland\n* Correspondence\n\nMarianne Udd, Department of Surgery, Helsinki University Hospital and Helsinki University, Helsinki, Finland.\n\nEmail: marianne.udd@hus.fi\n05 6 2017 7 2017 7 7 10.1002/brb3.2017.7.issue-7e0073731 3 2017 14 4 2017 © 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nContinuous levodopa‐carbidopa intestinal gel (LCIG) diminishes daily “off” time and dyskinesia in patients with advanced Parkinson′s disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG‐J).\n\nAim of the Study\nTo report the clinical outcome of LCIG in patients with advanced PD in the years 2006–2014 at Helsinki University Hospital.\n\nPatients and Methods\nLevodopa‐carbidopa intestinal gel treatment started following PEG‐J placement in patients with advanced PD after successful in‐hospital LCIG trial with a nasojejunal tube. Demographics, PEG‐J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed.\n\nResults [mean (SD)]\nSixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa‐equivalent daily dose (LEDD) had increased by 30% compared to pre‐LCIG LEDD. Sixty patients underwent a total of 156 PEG‐J procedures, and 48 patients (80%) had a total of 143 complications. Forty‐six patients (77%) had 119 PEG‐J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J‐tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow‐up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died.\n\nConclusion\nMost patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG‐J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.\n\ncomplicationduodopaLCIGmortalityParkinson's diseasePEG‐Jweight loss source-schema-version-number2.0component-idbrb3737cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:19.07.2017\n\n\nUdd \nM \n, \nLyytinen \nJ \n, \nEerola‐Rautio \nJ \n, et al. Problems related to levodopa‐carbidopa intestinal gel treatment in advanced Parkinson's disease . Brain Behav . 2017 ;7 :e00737\nhttps://doi.org/10.1002/brb3.737\n==== Body\n1 INTRODUCTION\nPatients with advanced Parkinson's disease (PD) suffer from daily motor fluctuations and dyskinesia. “On” time means periods of good motor control with no disturbing dyskinesia, while “off” time is periods of stiffness and poor mobility. Ideal medication reduces “off” time and minimizes dyskinesia. Combinations of levodopa with carbidopa or benserazide, dopamine agonists, MAO‐B inhibitors and COMT inhibitors are the standard treatment for PD (Horstink et al., 2006). In the advanced disease state, wearing off, on‐off phases, or dyskinesia lead to functional impairment (Ahlskog & Muenter, 2001). The short half‐life of oral levodopa and individual variation of gastric emptying in PD patients cause daily fluctuations in levodopa plasma concentration. Deep brain stimulation (DBS) (Deep Brain Stimulation for Parkinson's Disease Study, Group, 2001), apomorphine infusion (Trenkwalder et al., 2015) and continuous infusion of levodopa‐carbidopa intestinal gel (LCIG) (Nilsson, Nyholm, & Aquilonius, 2001) are device‐aided therapies that can diminish “off” ‐time and dyskinesia in advanced PD. DBS, LCIG and an apomorphine pump are considered only if a combinations of the aforementioned oral drugs is not sufficient. In Finland DBS has been available since 1995, and LCIG since 2006 with 100% reimbursement. Apomorphine pump has been available in Finland since April 2017.\n\nLevodopa‐carbidopa intestinal gel with a levodopa concentration of 20 mg/ml is administered via a portable pump that is connected to the PEG‐J, a percutaneous endoscopic gastrostomy (PEG) with a thinner inner J‐tube placed in the proximal jejunum. LCIG treatment ensures continuous dopaminergic stimulation and it significantly reduces daily motor fluctuations and dyskinesia compared to oral levodopa (Olanow et al., 2014). However, complications with the tube or the pump are common, presenting in 40%–96% of patients (Devos, 2009; Fernandez et al., 2013, 2015; Nyholm et al., 2008; Pickut, van der Linden, Dethy, Van De Maele, & de Beyl, 2014).\n\nThe aim of the present study was to analyze the outcome of long‐term LCIG treatment in advanced PD, paying special attention to complications and discontinuation of the treatment in the clinical setting.\n\n2 PATIENTS AND METHODS\nAltogether, 60 patients with advanced PD received LCIG therapy at Helsinki University Hospital between 2006 and 2014. A neurologist selected candidates for LCIG treatment i.e., patients who reported substantial daily motor fluctuations and dyskinesia that could not be sufficiently controlled with oral PD medication. Severe dementia, ongoing psychosis, and unresponsiveness to levodopa were exclusion criteria. The total daily oral doses of levodopa, amantadine, dopamine agonists and MAO‐B‐ and COMT‐inhibitors were converted to a morning dose and continuous daily infusion of LCIG. To assess the response to LCIG, the patients were admitted to neurological ward and had a nasojejunal tube (Flocare Bengmark® 10Fr, Nutricia, Netherlands) for 4–6 days of testing. A radiologist positioned the tube near the ligamentum of Treitz under fluoroscopic control. LCIG was administered with a pump via the nasojejunal tube, and the response to LCIG was assessed with diaries. If this testing phase was successful, the patient had a PEG‐J.\n\n2.1 PEG‐J procedure\nA PEG‐J tube (Freka® 15 Fr or 20 Fr PEG ‐tube and Freka® 9 Fr intestinal Tube, Fresenius Kabi, Cheshire, UK) was inserted under endoscopic and fluoroscopic control by gastroenterologic surgeons in the endoscopic unit using the pull‐through method (Gauderer, Ponsky, & Izant, 1980). Antibiotic prophylaxis (1.5 g cefuroxime, Zinacef®, GlaxoSmithKline, Espoo, Finland) and local anesthesia with lidocaine (10 mg/ml Lidocain®, Orion, Espoo, Finland) were administered, and conscious sedation was provided by an anesthesiologist. After placement of the PEG tube, the inner J tube was moved near the ligamentum of Treitz with rat‐tooth forceps. If this failed, a guidewire (Jagwire, Boston Scientific, Alajuela, Costa Rica) and a triple lumen balloon were passed to the duodenum, the balloon was retrieved and the J tube inserted over the guidewire. The position of the inner tube was controlled under fluoroscopy. The PEG‐J was connected to a portable infusion pump (CADD legacy 1400 Duodopa pump, Smits Medical ASD, St Paul, MN, USA).\n\n2.2 LCIG infusion in practice\nThe LCIG (20 mg/ml of levodopa and 5 mg/ml carbidopa; Duodopa®, Abbvie) dose optimization was carried out in the neurologic ward. All oral PD medication was usually stopped, with the exception of high‐dose dopamine agonists with positive clinical response. The morning bolus was followed by a continuous infusion. Additional doses were administered by the patient when they felt they were entering an “off” phase. Usually, infusion lasted 16 hr, supplemented with a sustained‐release oral dose of levodopa for the night. If necessary, night infusion was applied, with the infusion rate being about 40%–60% less than infusion during the day. Control phone calls were planned for 2–4 weeks after and control visits for 6 months after initiation of LCIG for clinical evaluation in the outpatient clinic. The patients were advised to gradually increase the daily infusion if several extra doses had to be taken daily. In cases of inner tube problems, the patients were advised to administer LCIG via PEG to the gastric space or to restart oral medication. If an infusion problem occurred, a scheduled admission to the neurological ward was arranged, with a subsequent endoscopic procedure to correct the tube problem.\n\n2.3 Data collection at baseline and during the follow‐up\nThe following data were collected: duration of PD, age at onset of PD, preceding PD medication, ASA (Physical Status Classification of the American Society of Anesthesiologists) class, body mass index (BMI), concomitant diseases, details of the PEG‐J procedure, living conditions (alone, with a spouse, in institutional care), a mini‐mental state examination (with MMSE ≥25 indicating normal cognition), a Hoehn and Yahr scale assessment, neurosurgical contraindications (coagulopathy, cognitive impairment). Also daily hours on LCIG, LCIG doses after 6 months, and any additional oral medication data were collected. At the end of the follow‐up in November 2015, information about weight loss (weight change as a percentage during follow‐up), living conditions and discontinuation of the LCIG treatment was gathered. The number of contacts with the stoma nurse, data of PEG‐J related (tube occlusion, accidental removal of inner tube, dislocation of the inner tube backwards into the stomach, tube breakage), peristomal (stoma leakage, granulation tissue around stoma, skin excoriation, abscess or infection, PEG tube hat buried in gastric wall, i.e., buried bumper syndrome (BBS)), or other (≥5% weight loss, gastric ulceration caused by inner tube, neurological) complications and mortality were collected from the patient files for the study. Underweight was defined as a BMI of <18.5 m2/kg, normal weight as a BMI 18.5–25 m2/kg, and overweight as a BMI of >25 m2/kg.\n\n2.4 Informed consent statement\nThe study was approved by the hospital ethics committee. Data extraction occurred retrospectively from hospital medical records. According to Finnish law, retrospective research using hospital medical files does not require informed consent from the study subjects.\n\n2.5 Statistics\nThe results are reported as means and standard deviation (SD). The significance of differences in categorical data was determined using Fisher's exact test. The Mann–Whitney U test was used to discover the differences in continuous variables. A level of p < .05 was regarded as statistically significant, and two tailed tests were used. Statistical calculations were generated using IBM SPSS Statistics 21 (International Business Machines Corporation, Endicott, NY, USA).\n\n3 RESULTS\nMean age at onset of PD was 56 (8) years, and the duration of PD was 11 (4) years before LCIG treatment. There were 32 men (53%) and 28 women (47%) with a mean age of 68 (7) years, and 27 participants (45%) were 70 or older. Baseline characteristics are presented in Table 1. The mean Hoehn and Yahr score in the “on” phase was 2.7 (0.7). At the onset of LCIG treatment, all the patients had been on levodopa only, or a combination of amantadine, a dopamine agonist, and MAO‐B‐ or COMT‐ inhibitors, with a mean levodopa‐equivalent daily dose (LEDD) of 1,266 (441) mg. Ten patients (17%) were taking only levodopa, 18 (31%) were taking two drugs and 30 (52%) had three or more different drugs daily. An MMSE test was performed on 48 patients prior to LCIG treatment. The mean MMSE score was 26 (3). Altogether, 29 patients refused or had contraindications for DBS treatment. The details of the PEG‐J procedure are presented in Table 2.\n\nTable 1 Baseline characteristics of PD patients on LCIG treatment\n\nDemographics\t\nn = 60\t\nASA I\t0\t\nASA II\t3 (5%)\t\nASA III\t51 (85%)\t\nASA IV\t6 (10%)\t\nCoronary/‐heart disease\t17 (28%)\t\nDiabetes\t8 (13%)\t\nPsychiatric diagnosis\t11 (18%)\t\nMMSE ≤24\t11 (23%)\t\nHoehn and Yahr score on phase ≥4\t6 (10%)\t\nLives with a spouse\t44 (73%)\t\nLives alone\t12 (20%)\t\nIn sheltered housing with assistance\t4 (7%)\t\nWalker as mobility aid\t15 (25%)\t\nWheelchair or crutches as mobility aid\t6 (11%)\t\nPD, Parkinson's disease; LCIG, levodopa‐carbidopa intestinal gel; ASA, data of physical status classification of the American Society of Anesthesiologists ASA class; MMSE, mini‐mental state examination.\n\nJohn Wiley & Sons, LtdTable 2 PEG‐J placement procedure in 60 patients\n\nTime from nasojejunal test tube placement to PEG‐J placement; days; mean (SD)\t6.5 (2.7)\t\nTotal hospital stay, days; mean (SD)\t11 (4)\t\nHospital stay after PEG‐J placement, days\t3.9 (3.9)\t\nLength of the procedure, min; mean (SD)\t31 (16)\t\nAntibiotic prophylaxis\t48 (87%)\t\nPEG‐J: Fresenius Freka® 15 Fr\t51 (85%)\t\nPEG‐J: Boston® 20 Fr\t9 (15%)\t\nInner tube in the descending or transverse duodenum\t6 (10%)\t\nInner tube in the ligament of Treitz\t54 (90%)\t\nPEG‐J, percutaneous endoscopic gastrostomy with jejunal tube; SD, standard deviation.\n\nJohn Wiley & Sons, Ltd3.1 LCIG dose\nAfter discharge, 51 patients (85%) had daily LCIG infusion, and nine cases (15%) were 24 hr a day. The mean daily LCIG dose was 1,651 (595) mg. At 6 months, 42 patients (78%) had daily infusion and 12 (22%) had 24‐hr infusion. In most cases (44), the LEDD had increased by 505 (304) mg compared with the baseline. In nine patients, the LEDD had decreased by 255 (126) mg. Doses of LCIG at baseline and 6 months were: morning bolus 191 (67) mg vs. 170 (71) mg, continuous infusion 73 (27) mg/hr vs. 81 (29) mg/hr (6 a.m.–10 p.m.) and 57 (26) mg/hr vs. 72 (43) mg/hr (10 p.m.–6 a.m.), correspondingly.\n\nAt the end of the follow‐up period of 33 (24) months, 38 patients (63%) were on LCIG, 7 (12%) had been on LCIG until death, 13 (22%) had discontinued LCIG and were alive, and two patients (3%) discontinued LCIG and died later.\n\nThirty‐two patients were on LCIG for more than 2 years, and 12 patients for more than 4 years. Fifty‐three patients (90%) felt that LCIG treatment still substantially alleviated motor symptoms, when questioned at 6 months and beyond.\n\n3.2 Changes in weight, living conditions and need for walking devices during LCIG treatment\nAt baseline, the mean BMI of the patients was 24.7 (4.2) kg/m2: only three patients (5%) were underweight, 31 (57%) were normal weight and 26 (43%) were overweight. At the end of the follow‐up, eight patients (13%) were underweight, 31 (52%) were normal weight and 21 (35%) were overweight. The weight change as a percentage was −3.3% (10.7%) in 25.7 (23.1) months. Eighteen patients (30%) had weight loss of ≥5%, and in 12 patients (20%), weight loss was ≥10%. One patient had fatal weight loss despite discontinuation of LCIG. Body CT did not show any malignancy. The autopsy failed to reveal any clear cause for his deterioration. Two patients had peripheral neuropathy prior to LCIG, probably due to diabetes and spinal stenosis.\n\nAt the end of the follow‐up, 38 patients (66%) were still living at home with their spouse or alone, 17 (29%) were in institutional care, (mainly sheltered housing with 24‐hr assistance), and three patients had intervals at home and in institutions. Nine patients originally living with their spouse (21%) and four originally living alone (33%) had moved to sheltered housing. The need to use a walker increased by 40%, (n = 21, 37%) and a wheelchair by 50% (n = 6; 11%), and two patients became bedridden.\n\n3.3 Discontinuation\nCognitive decline or dementia at the baseline or appearance of these symptoms during follow up were the most common causes of infusion withdrawal, occurring in seven patients after 27 (25) months of LCIG. In two bedridden patients living in institutions, LCIG was stopped after 38 (12) months. One patient was suffering from stoma problems and discontinued the treatment at 19 months. Two patients (3.3%) stopped LCIG after 3 months and 5 months because of inefficacy. One patient subjectively felt dizziness during LCIG treatment and decided to discontinue the LCIG infusion after a month, although clinical examination showed no signs of either postural instability or orthostatic hypotension. Altogether, after a mean of 21 (21) months, LCIG was discontinued in 15 patients, and in 11 cases the reason was recurrent removal of the inner tube by the patient.\n\n3.4 Complications\nSixty patients underwent a total of 156 endoscopic procedures. An additional 96 endoscopic procedures following 60 PEG‐J placements are presented in Table 3, and complications related to LCIG treatment are shown in Table 4. There were 48 patients (80%) with a total of 143 complications, and only 12 patients with no complications. Altogether, 46 patients (77%) had a total of 119 PEG‐J or peristomal complications, and 22 (37%) had a total of 25 other complications. On average, patients had 2.4 (2.1) complications. In 30 days after PEG‐J, 11 patients (18%) had complication (six peristomal infections, one granulation, one gastric hematoma, one nonspecific infection, one knot and occlusion, and one disorientation). Thirty‐one patients visited a stoma nurse a total of 121 times. Accidental removal of the inner tube occurred significantly more often in patients with cognitive decline (MMSE <24), than in those without it: 8 (73%) vs. 12 (35%); p = .034. There were no peritonitis cases during the follow‐up.\n\nTable 3 Additional procedures after PEG‐J placement in the endoscopy unit (n = 96)\n\nHospital stay, days; mean(SD)\t2.3 (3.7)\t\nLength of the procedure, min; mean (SD)\t19 (11)\t\nIndications for the procedure\t\nAccidental removal of inner tube\t37 (38%)\t\nTube occlusion\t27 (29%)\t\nTube break\t14 (15%)\t\nStoma leak\t4 (4%)\t\nDislocation of the inner tube backwards into the stomach\t2 (2%)\t\nThicker PEG‐J for nutrition\t4 (4%)\t\nDiscontinuation of the treatment\t8 (8%)\t\nProcedures: n = 96\t\nInner tube placement or exchange\t45 (47%)\t\nPEG‐J tube exchange\t25 (26%)\t\nTesting the tube, checking with fluoroscopy or gastroscopy, exchanging the caps\t13 (14%)\t\nRemoval of the PEG‐J systema\n\t13 (14%)\t\nPEG‐J, percutaneous endoscopic gastrostomy‐jejunal tube; SD, standard deviation.\n\na Of 15 patients discontinuing LCIG, two patients used the PEG for nutrition and it was not removed.\n\nJohn Wiley & Sons, LtdTable 4 Complications in 60 patients on LCIG\n\nComplication\t\nn = 60\t\nPeristomal complications:\t\nBuried PEG bumper\t1 (1%)\t\nSkin problems, leaking stoma\t12 (20%)\t\nNonspecific infection\t4 (7%)\t\nSkin infection, abscess\t5 (8%)\t\nGranulation tissue\t21 (35%)\t\nTube complications:\t\nTube occlusion\t13 (22%)\t\nAccidental removal of inner tube\t23 (38%)\t\nDislocation of the inner tube backwards into the stomach\t5 (8%)\t\nTube break\t11 (18%)\t\nOther complications:\t\nWeight loss ≥5%\t18 (30%)\t\nNeurologic symptoms\t3 (5%)\t\nPump issue\t3 (5%)\t\nPeritonitis\t0\t\nLCIG, levodopa‐carbidopa intestinal gel.\n\nJohn Wiley & Sons, Ltd3.5 Mortality\nAccording to death certificates provided by Statistics Finland, there were no PEG‐J related complications or deaths. Altogether, nine patients died, seven of whom were on LCIG until death. Two patients died 3.7 and 21.5 months after discontinuing LCIG, respectively. The time from the start of LCIG to death was 26.6 (14) months. The causes of death were defined by clinical examination in four patients and by clinical autopsy in five patients. The immediate causes of death were pneumonia (n = 4), advanced PD (n = 2), coronary heart disease or insufficiency (n = 2) and pulmonary embolism (n = 1). The underlying causes of death were PD (n = 7) and coronary heart disease (n = 2).\n\nBody mass index at onset was significantly higher in those alive at the end of the follow‐up compared to those who died: 25.1(4.4) vs. 22.2(3.4); p = .043. Similarly, BMI at the latest follow‐up visit was significantly higher in those alive at the end of the follow‐up than in those who died during the follow‐up, at 24.3 (4.0) vs. 18.9 (3.1); p = .001. Four underweight patients (44%) died, compared to five patients (8%) with normal weight or overweight; p = .013.\n\n4 DISCUSSION\nLevodopa‐carbidopa intestinal gel treatment has proved to be effective in reducing levodopa‐related dyskinesia and diminishing off time compared to oral medication, leading to improvement in the quality of life (Antonini, Yegin, Preda, Bergmann, & Poewe, 2015; Lopiano et al., 2016; Olanow et al., 2014; Wirdefeldt, Odin, & Nyholm, 2016). We present data on LCIG therapy, focusing on complications. The majority of our patients were satisfied with the infusion during follow‐up. There were, however, numerous tube and stoma complications related to LCIG, as reported previously (Fernandez et al., 2015; Lang et al., 2016; Nilsson et al., 2001).\n\nIn most of our patients, LEDD was increased at 6 months compared to baseline. The LEDD increase may be caused by disease progression. We had 12 patients (20%) with their LCIG pump running for 24 hr. That is slightly more than previously reported by Devos et al. (10% LCIG for 24 hr) (Devos, 2009). One study showed a quite stable LEDD on LCIG for 12 months (Antonini et al., 2015).\n\nIn some studies, dementia was an exclusion criterion, and only patients with an MMSE of 28–29 were included (Epstein et al., 2016; Fernandez et al., 2015). In a French multicentre study (Devos, 2009), 50% of the patients on LCIG had cognitive disorders suggestive of PD dementia. We found LCIG suitable for patients with mild dementia living with a motivated spouse. However, there was more accidental tube removal in patients with cognitive decline. Hence, patients with dementia living alone appear not to be suitable candidates for LCIG. Despite the LCIG treatment, 29% of our patients were in institutional care, mainly sheltered housing with 24‐hr assistance at the end of the follow‐up.\n\nSeveral technical problems and complications increase the annual admission rate and contact with the hospital (Nyholm et al., 2008). Complications with the PEG‐J tube (Devos, 2009; Fernandez et al., 2013; Nyholm et al., 2008) are similar to complications related to PEG for feeding purposes (Schapiro & Edmundowicz, 1996; Udd et al., 2015). The risk of peritonitis has varied between zero and 4% (Devos, 2009; Epstein et al., 2016; Lang et al., 2016; Palhagen et al., 2016), and other serious complications like colonic perforations, gastropleural fistula (Klostermann et al., 2012) and liver injury (Pickut et al., 2014), have also been described. In our material, we did not have any peritonitis, nor any need for emergency abdominal surgery due to LCIG complications. A peristomal infection risk of 8% is comparable with the literature: 10%–20% (Devos, 2009; Epstein et al., 2016; Fernandez et al., 2015; Olanow et al., 2014). Inner tube complications were mostly accidental removal, kinking or dislocation of the tube occurring during the LCIG treatment in physically active patients, sometimes suffering from disorientation (Devos, 2009; Fernandez et al., 2013; Nyholm et al., 2008; Pickut et al., 2014). We did not find any cases of inner tube‐induced duodenal decubitus ulcer (Martino et al., 2016), or bezoar sometimes present in these patients. Our results showed that 13 patients had a total of 27 tube occlusions, and eight of them (61%) had altogether ten knots in the inner tube. Previously, only three case reports of five patients with knotting of the inner tube had been published (del‐Hoyo‐Francisco et al., 2015; Krones, Zollner, & Petritsch, 2012; Nyholm et al., 2008). The Freka® intestinal tube has an angled, C‐shaped tip, and this may predispose the tube to knots (Figure 1). The present results showing that removal of the inner tube occurs more often in patients with dementia are supported by previous findings (Devos, 2009). Logically, among patients with no dementia, the rate is lower (Epstein et al., 2016; Fernandez et al., 2015).\n\nFigure 1 Naive and knotted jejunal tube\n\nThe triangular external fixation plate of the Freka® PEG‐J tube is suboptimal, because it glides along the PEG tube, allowing the PEG to move back and forth. This movement may even predispose the patient to peritonitis in the first days when the stoma is maturing (Epstein et al., 2016). The skin around the peristomal area may become irritated by leaking gastric fluids. Granulation formation needs referral to a stoma nurse. Granulation tissue was more common in our patients (35%) compared to other series (20%–22%) (Epstein et al., 2016; Lang et al., 2016).\n\nWeight loss is an adverse event increasing the risk of death, and is partly associated with the natural course of PD. One third of our patients had ≥5% weight loss during the follow‐up with one fatal weight loss despite discontinuation of LCIG. Decreased weight has been observed in 5%–10% of LCIG patients (Antonini et al., 2015; Merola et al., 2016). The mechanism for weight loss in LCIG remains ambiguous. Monitoring weight during LCIG treatment is essential to avoid serious weight loss.\n\nEighty percent of the patients had complications leading to multiple endoscopic procedures, but still 90% were satisfied with the treatment. Some of the complications may therefore be related to the suboptimal devices and tubes. A new T‐port was found to be well tolerated, and it had a low number of tube problems, but proper cleaning and local treatment of the stoma site were necessary (van Laar, Nyholm, & Nyman, 2016). The use of a T‐port is not widely spread, though.\n\nCurrently, there are no guidelines for withdrawal of LCIG. If the patient is bedridden, disoriented and already needs maximal care, LCIG probably may not give any significant health benefit. Several removals of the inner tube by a patient during the treatment suggest that the mental condition of that patient has significantly deteriorated. In these cases, discontinuation of LCIG should be individually considered. Further, several replacements of the inner tube increase the burden of already limited hospital resources. Continuous weight loss can even be a fatal complication, and therefore needs monitoring. Close co‐operation between neurological and endoscopic units is required, and units must be prepared for common and recurrent PEG‐J problems when LCIG treatment for advanced PD is carried out.\n\nCONFLICTS OF INTEREST\nMarianne Udd received a one‐month researcher's salary from the Helsinki University Hospital Research Fund. The authors have no conflicts of interest to disclose.\n\nACKNOWLEDGMENTS\nAll co‐authors have reviewed and approve the content of the manuscript. The Brain and Behaviour requirements for authorship have been met, and there is no ghost‐writing by anyone not named on the author list. We confirm that the manuscript is not under review and has not been accepted for publication elsewhere.\n==== Refs\nREFERENCES\n\n\nAhlskog , J. E. \n, & \nMuenter , M. D. \n (2001 ). Frequency of levodopa‐related dyskinesias and motor fluctuations as estimated from the cumulative literature . 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Gastrointestinal Endoscopy Clinics of North America , 6 (2 ), 409 –422 .8673334 \n\n\nTrenkwalder , C. \n, \nChaudhuri , K. R. \n, \nGarcia Ruiz , P. J. \n, \nLeWitt , P. \n, \nKatzenschlager , R. \n, \nSixel‐Doring , F. \n, … \nWenzel , K. \n (2015 ). Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease–Clinical practice recommendations . Parkinsonism & Related Disorders , 21 (9 ), 1023 –1030 .26189414 \n\n\nUdd , M. \n, \nLindstrom , O. \n, \nMustonen , H. \n, \nBack , L. \n, \nHalttunen , J. \n, & \nKylanpaa , L. \n (2015 ). Assessment of indications for percutaneous endoscopic gastrostomy–development of a predictive model . Scandinavian Journal of Gastroenterology , 50 (2 ), 245 –252 .25540954 \n\n\nWirdefeldt , K. \n, \nOdin , P. \n, & \nNyholm , D. \n (2016 ). Levodopa‐carbidopa intestinal gel in patients with Parkinson's Disease: A systematic review . CNS Drugs , 30 (5 ), 381 –404 .27138916\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "7(7)", "journal": "Brain and behavior", "keywords": "LCIG; PEG‐J; Parkinson's disease; complication; duodopa; mortality; weight loss", "medline_ta": "Brain Behav", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D012189:Retrospective Studies; D016896:Treatment Outcome; D015431:Weight Loss", "nlm_unique_id": "101570837", "other_id": null, "pages": "e00737", "pmc": null, "pmid": "28729942", "pubdate": "2017-07", "publication_types": "D016428:Journal Article", "references": "22298101;19253412;24379105;18382177;23192929;24361112;25545465;6780678;17038031;11575287;27421834;11903087;23287001;27030949;27614656;8673334;27138916;26189414;28729942;26213103;25540954;11391738;25585993;26695437;27215392;25952811;27318707", "title": "Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease.", "title_normalized": "problems related to levodopa carbidopa intestinal gel treatment in advanced parkinson s disease" }	[ { "companynumb": "FI-ABBVIE-12P-055-0952193-00", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "203952", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DUODOPA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Parkinson^s disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "UDD M, LYYTINEN J, PEKKONEN E. 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{ "abstract": "Tumor necrosis factor (TNF) is a major cytokine in the pathogenesis of inflammatory bowel disease (IBD), and TNF inhibition is a cornerstone of contemporary IBD therapy. However, paradoxical induction of IBD has recently been reported upon treatment of rheumatologic disorders with TNF inhibitors. In previous cases, induction of IBD was associated with one single drug and IBD was successfully managed by switching TNF inhibitors. We report the case of a patient with juvenile rheumatoid arthritis under long-term treatment with etanercept. After switching TNF inhibition to adalimumab, symptoms of Crohn's disease (CD) occurred and the diagnosis of CD was established by endoscopy. Further treatment with adalimumab and subsequently infliximab aggravated the abdominal symptoms, necessitating ileocecal resection, after which symptoms resolved for several months. Etanercept treatment due to recurrent rheumatologic symptoms was followed by recurrent CD symptoms and findings, which resolved upon discontinuation of etanercept. This case suggests that induction, aggravation and recurrence of IBD can be rare class effects of TNF inhibition.", "affiliations": "Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Department of Visceral and Transplant Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.", "authors": "Zeitz\|Jonas\|J\|;Enderlin\|Susann\|S\|;Biedermann\|Luc\|L\|;Turina\|Matthias\|M\|;Leibl\|Sebastian\|S\|;Prakash\|Meher\|M\|;Rogler\|Gerhard\|G\|;Misselwitz\|Benjamin\|B\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000381637", "fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000381637crg-0009-0106Published online: April, 2015New Onset, Aggravation and Recurrence of Crohn's Disease upon Treatment with Three Different Tumor Necrosis Factor Inhibitors Zeitz Jonas aEnderlin Susann bBiedermann Luc aTurina Matthias cLeibl Sebastian dPrakash Meher aRogler Gerhard aMisselwitz Benjamin aaDivision of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandbDivision of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandcDepartment of Visceral and Transplant Surgery, University Hospital Zurich, University of Zurich, Zurich, SwitzerlanddDivision of Pathology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandBenjamin Misselwitz, Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091 Zurich (Switzerland), E-Mail benjamin.misselwitz@usz.chJan-Apr 2015 24 4 2015 24 4 2015 9 1 106 112 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Tumor necrosis factor (TNF) is a major cytokine in the pathogenesis of inflammatory bowel disease (IBD), and TNF inhibition is a cornerstone of contemporary IBD therapy. However, paradoxical induction of IBD has recently been reported upon treatment of rheumatologic disorders with TNF inhibitors. In previous cases, induction of IBD was associated with one single drug and IBD was successfully managed by switching TNF inhibitors. We report the case of a patient with juvenile rheumatoid arthritis under long-term treatment with etanercept. After switching TNF inhibition to adalimumab, symptoms of Crohn's disease (CD) occurred and the diagnosis of CD was established by endoscopy. Further treatment with adalimumab and subsequently infliximab aggravated the abdominal symptoms, necessitating ileocecal resection, after which symptoms resolved for several months. Etanercept treatment due to recurrent rheumatologic symptoms was followed by recurrent CD symptoms and findings, which resolved upon discontinuation of etanercept. This case suggests that induction, aggravation and recurrence of IBD can be rare class effects of TNF inhibition.\n\nKey Words\nInflammatory bowel diseaseCrohn's diseaseTumor necrosis factor inhibitionAutoimmune-like syndromes\n==== Body\nIntroduction\nTumor necrosis factor (TNF) plays a central role in the pathogenesis of inflammatory bowel disease (IBD), and the introduction of TNF inhibitors has substantially broadened the therapeutic options in IBD [1]. Available monoclonal antibodies which are effective for the treatment of Crohn's disease (CD) and ulcerative colitis include infliximab and adalimumab [2]. In contrast etanercept, a fusion protein of the human soluble TNF receptor p75 with the Fc fragment of human immunoglobulin G1, was shown to be safe but not effective in CD [3]. The reasons for this differential effect of infliximab/adalimumab and etanercept are not understood, but might include complement-dependent cytotoxicity and induction of apoptosis by infliximab/adalimumab, but not by etanercept. Vice versa, lymphotoxin is bound and neutralized by etanercept, but not the antibodies [4].\n\nTherapy with TNF inhibitors has an acceptable safety profile and besides infusion reactions, the adverse events of TNF inhibitor treatment are mainly infectious complications, including tuberculosis, as might be expected from their mode of action [5]. Paradoxical immune activation by TNF inhibitors has also been described, and autoimmune disorders, including psoriasis, vasculitis, systemic lupus erythematosus, interstitial lung disease and sarcoidosis, have been reported as adverse events of TNF inhibitor treatment [6]. The mechanisms of autoimmune-like syndromes during TNF blockade have not be clarified, but autoimmune-like syndromes might be caused by cytotoxicity of the drugs, increase of interferon-α levels by TNF, dysregulation of T cells and unrecognized infectious complications. Furthermore, direct or indirect effects of TNF inhibitors might induce exposure towards autoantigens, including self-DNA or self-RNA, which could act as endogenous ligands of Toll-like receptors and lead to autoimmunity [7].\n\nParadoxical induction of IBD by the TNF inhibitor etanercept has been described in seminal case reports and systematic analyses [8, 9]. IBD as an adverse event of treatment is not limited to etanercept treatment, since recent case series also included cases of IBD induced by infliximab or adalimumab [10]. However, in the cases described, new-onset IBD could be treated by switching TNF inhibitors, usually to infliximab or adalimumab, and idiosyncratic effects of the culprit drugs could not be excluded. We report a case with new onset, progression and recurrence of CD upon treatment with three different TNF inhibitors, suggesting paradoxical induction of IBD as a class effect of TNF inhibitors.\n\nCase Presentation\nA 19-year-old man presented to our division for the management of severe right lower quadrant pain. His previous history was remarkable for juvenile rheumatoid arthritis starting at 12 years of age, involving the sacroiliac and mandibular joint as well as the right ankle and hip. He was tested positive for HLA-B27, but tests for antinuclear antibodies and rheumatoid factor proved to be negative. At 16 years of age etanercept 50 mg s.c. was started which initially relieved the symptoms, so the dose was reduced to every 2 weeks after 1 year of treatment. However, 1 year later the joint pain recurred and was refractory to etanercept dose escalation (weekly) and add-on naproxen. Two months before the onset of abdominal pain the treatment regime was changed to adalimumab 40 mg s.c. every 2 weeks and the patient remained free of rheumatologic problems for the next year.\n\nDuring evaluation for abdominal pain, lower right quadrant tenderness and a palpable tumor were noted. Blood work revealed systemic inflammation (C-reactive protein 46 mg/l and leukocytosis with 13.7 × 109 leucocytes per liter with 84% neutrophils). Ultrasound and computed tomography suggested terminal ileitis and abdominal lymphadenopathy. Stool tests for microorganisms including Clostridium difficile were negative. Colonoscopy demonstrated an ulcerated ileocecal valve with a narrow opening that could not be intubated. Histology confirmed granulomatous inflammation and acute inflammation, and all tests for infectious diseases, including acid-fast staining, mycobacteria cultures and immunohistochemistry for cytomegalovirus, were negative.\n\nSince the patient's presentation was consistent with new-onset CD, we continued adalimumab treatment and started budesonide at 9 mg/day. Subsequently, abdominal pain improved; however, surveillance of small bowel inflammation by abdominal ultrasound continued to show wall thickening >6 mm, consistent with active inflammation, and budesonide was increased to 15 mg/day. Due to recurrent abdominal symptoms treatment was switched to infliximab 5 mg/kg body weight, but abdominal pain only temporarily improved and recurred only 3 months after starting infliximab. The patient was now complaining of constant abdominal pain and had lost 12 kg of body weight (body mass index 16 kg/m2). Magnetic resonance imaging revealed chronic terminal ileitis and a complex fistula system. In hospital parenteral nutrition was started, infliximab was stopped, and 9 months after the onset of abdominal pain, right-sided colectomy with an ileocolic anastomosis was performed (fig. 1). The immediate postoperative course was unremarkable; the patient remained free of symptoms and body weight increased.\n\nThree months after surgery, joint inflammation recurred in the hips, shoulders, right foot, lumbar spine and sacroiliac joint. Due to limited therapeutic options for the treatment of ileosacral arthritis, etanercept 50 mg s.c. weekly was restarted after careful discussion with the patient. Etanercept immediately relived joint pains, but 14 days after restarting the TNF inhibitor abdominal pain recurred, accompanied by an increase in calprotectin levels. Colonoscopy revealed multiple ulcers at the ileocolic anastomosis and histology confirmed ulceration. Abdominal pain slowly resolved after etanercept had been discontinued. The clinical course is summarized in figure 2.\n\nDiscussion and Conclusions\nIn our patient induction, aggravation and recurrence of CD occurred during treatment with three different TNF inhibitors (adalimumab, infliximab and etanercept). According to the Naranjo algorithm [11], a consensus algorithm to estimate the probability of causality in a suspected drug-induced clinical event, a definite association between TNF inhibitor treatment and CD as an adverse drug event is present in our patient (10 out of 13 possible points). Importantly, there has been no alternative explanation of IBD in our patient with a negative family history for IBD and only a brief period of naproxen treatment, which had been discontinued weeks before the initial onset of abdominal pain. However, some limitations of the Naranjo algorithm exist and some ambiguity remains: Following a recent analysis of new-onset IBD as an adverse event of TNF inhibitor treatment, we did not score juvenile idiopathic arthritis as an alternative explanation for IBD in our patient [12]. The possibility of joint involvement as an extraintestinal manifestation of IBD preceding the onset of CD for several years seems unlikely but cannot be rigorously excluded. For consistency, the Naranjo score was applied as in the previous larger study [12].\n\nProof for an association of IBD with TNF treatment is strongest for etanercept. In addition to seminal case reports, larger case series have now been published. Thereby, in a report from a European etanercept registry for treatment of juvenile idiopathic arthritis, 13 cases of new-onset IBD (including 9 cases with CD) were noted. The authors calculated a 43-fold increased risk for IBD compared to the control population. Of note, 10 of the patients were subsequently treated with another TNF inhibitor (5 each, infliximab and adalimumab) [13]. A second case series from France identified 8 patients with juvenile idiopathic arthritis and etanercept treatment (5 cases with CD and 3 cases with unclassified colitis). The clinical course of all patients was favorable upon discontinuation of etanercept; 6 of 8 patients were successfully treated with infliximab [9].\n\nWithin the last years, infliximab and adalimumab have increasingly been used for the treatment of rheumatic disorders and, likely due to increased patient exposure, evidence of paradoxical induction of IBD was also observed for these antibodies. A recent French series described 16 patients with rheumatoid arthritis and new-onset IBD under TNF inhibitor treatment (14 cases with etanercept, 2 with adalimumab). Similarly to the previous series, most of the patients had CD (8 and 6 cases with CD and Crohn's-like disease, respectively, and 1 case with unclassified colitis), and all patients could be successfully treated by switching the TNF inhibitor to infliximab or adalimumab [10]. Finally, a recent publication analyzing all adverse events regarding TNF inhibitors reported to the FDA described 158 cases of new-onset IBD. Most of the cases involved etanercept, but 28 cases of infliximab, 24 cases of adalimumab and 1 case of golimumab were listed. 111 of the associations were regarded as ‘possible’ and 47 as ‘probable’ according to the Naranjo algorithm [12].\n\nTaken together, the various case reports and case series reporting new-onset IBD upon etanercept treatment strongly suggest that etanercept can rarely trigger IBD in susceptible patients. Paradoxical induction of IBD by infliximab and adalimumab is also likely, even though the evidence is weaker. Therefore, TNF inhibition seems to have paradoxical pro-inflammatory properties which are usually extinguished by its anti-inflammatory effects. It is tempting to speculate that etanercept, which has no proven therapeutic effects against CD, can cause overt mucosal inflammation more often than infliximab or adalimumab, which are highly effective against IBD. Following this model, only in those few patients for whom the inflammatory process is completely resistant to TNF inhibition can inflammation progress to clinically overt CD.\n\nSpecific risk factors for the development of paradoxical IBD in patients exposed to etanercept or infliximab/adalimumab remain to be elucidated. In addition, it is unknown why TNF inhibition would trigger mainly CD or unclassified colitis. In any case, our report adds evidence regarding the great variability in the pathways utilized for the inflammatory process in different patients and suggests that TNF can be protective in at least a few patients [14].\n\nThe management of IBD cases triggered by TNF inhibitors is largely identical to that of classical IBD cases, and in addition to discontinuation of the offending drug, standard IBD treatment should be applied [15]. When appropriate, switching the TNF inhibitor also seems to be safe; however, if symptoms persist or worsen even upon treatment with a second inhibitor (as in our patient), alternative treatment options should be pursued.\n\nIn summary, we present the first case of a patient in whom the onset, aggravation and recurrence of CD were triggered by TNF inhibition with three different TNF inhibitors, and our results point to CD as a rare adverse event and a class effect of TNF inhibitors.\n\nAuthor Contributions\nB. Misselwitz and J. Zeitz drafted the manuscript. G. Rogler, S. Enderlin, L. Biedermann, M. Turina, S. Leibl and M. Prakash edited the manuscript for important intellectual content. M. Prakash, B. Misselwitz, M. Turina and S. Leibl prepared the figures. All authors read and approved the final version of the manuscript.\n\nDisclosure Statement\nB. Misselwitz has received travel grants from Vifor and Novartis and speaker's honoraria from MSD and Tillots. L. Biedermann has received research support from UCB, travel grants from MSD, Abbvie and Vifor, and fees for consulting/advisory boards from MSD, Abbvie and UCB. G. Rogler has consulted to Abbott, Abbvie, Boehringer, Calypso, FALK, Genentech, Essex/MSD, Novartis, Pfizer, Roche, UCB, Takeda (Switzerland), Tillots and Vifor, has received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB, and Vifor, and has received educational grants and research grants from Abbot, Abbvie, Ardeypharm, Essex/MSD, FALK, Flamentera, Novartis, Roche, Tillots, UCB and Zeller. J. Zeitz has received a research grant from Abbvie. S. Leibl, S. Enderlin, M. Turina and M. Prakash have no conflict of interests.\n\nFig. 1 Surgical specimen. a Macroscopic view. b Hematoxylin and eosin staining at 5-fold magnification revealing a fissure, transmural inflammation and architectural changes of the surrounding mucosa. c Hematoxylin and eosin staining at 100-fold magnification revealing non-caseating granulomas within a draining lymph node.\n\nFig. 2 a Overview of the clinical course. The time course of various pharmacological treatments and clinical symptoms is indicated. The time points of the first (C1) and second (C2) colonoscopy and the time point of surgery are marked. b Serum levels of C-reactive protein (CRP). c Levels of stool calprotectin.\n==== Refs\nReferences\n1 Sandborn WJ Targan SR Biologic therapy of inflammatory bowel disease Gastroenterology 2002 122 1592 1608 12016425 \n2 Ford AC Sandborn WJ Khan KJ Hanauer SB Talley NJ Moayyedi P Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis Am J Gastroenterol; quiz 660 2011 106 644 659 \n3 Sandborn WJ Hanauer SB Katz S Safdi M Wolf DG Baerg RD Tremaine WJ Johnson T Diehl NN Zinsmeister AR Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial Gastroenterology 2001 121 1088 1094 11677200 \n4 Marotte H Cimaz R Etanercept – TNF receptor and IgG1 Fc fusion protein: is it different from other TNF blockers? Expert Opin Biol Ther 2014 14 569 572 24611432 \n5 Targownik LE Bernstein CN Infectious and malignant complications of TNF inhibitor therapy in IBD Am J Gastroenterol; quiz 1843 2013 108 1835 1842 \n6 Perez-Alvarez R Perez-de-Lis M Ramos-Casals M BIOGEAS study group: Biologics-induced autoimmune diseases Curr Opin Rheumatol 2013 25 56 64 23114587 \n7 Prinz JC Autoimmune-like syndromes during TNF blockade: does infection have a role? Nat Rev Rheumatol 2011 7 429 434 21448162 \n8 Wiegering V Morbach H Dick A Girschick HJ Crohn's disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature Rheumatol Int 2010 30 801 804 19506877 \n9 Dallocchio A Canioni D Ruemmele F Duquesne A Scoazec JY Bouvier R Paraf F Languepin J Wouters CH Guillot M Quartier P Bader-Meunier B SOFREMIP: Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study Rheumatology (Oxford) 2010 49 1694 1698 20472717 \n10 Toussirot E Houvenagel E Goëb V Fouache D Martin A Le Dantec P Dernis E Wendling D Ansemant T Berthelot JM Bader-Meunier B Kantelip B Le CRI: Development of inflammatory bowel disease during anti-TNF-α therapy for inflammatory rheumatic disease: a nationwide series Joint Bone Spine 2012 79 457 463 22088934 \n11 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508 \n12 Krishnan A Stobaugh DJ Deepak P Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis Rheumatol Int 2015 35 661 668 25228459 \n13 Van Dijken TD Vastert SJ Gerloni VM Pontikaki I Linnemann K Girschick H Armbrust W Minden K Prince FH Kokke FT Nieuwenhuis EE Horneff G Wulffraat NM Development of inflammatory bowel disease in patients with juvenile idiopathic arthritis treated with etanercept J Rheumatol 2011 38 1441 1446 21459936 \n14 Slebioda TJ Kmiec Z Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease Mediators Inflamm 2014 2014 325129 25045210 \n15 Dignass A Van Assche G Lindsay JO Lémann M Söderholm J Colombel JF Danese S D'Hoore A Gassull M Gomollón F Hommes DW Michetti P O'Morain C Oresland T Windsor A Stange EF Travis SP European Crohn's and Colitis Organisation (ECCO): The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management J Crohns Colitis 2010 4 28 62 21122489\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-0631", "issue": "9(1)", "journal": "Case reports in gastroenterology", "keywords": "Autoimmune-like syndromes; Crohn's disease; Inflammatory bowel disease; Tumor necrosis factor inhibition", "medline_ta": "Case Rep Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101474819", "other_id": null, "pages": "106-12", "pmc": null, "pmid": "26034472", "pubdate": "2015", "publication_types": "D002363:Case Reports", "references": "21122489;21459936;12016425;19506877;22088934;21448162;11677200;25045210;20472717;24611432;24042192;25228459;7249508;21407183;23114587", "title": "New Onset, Aggravation and Recurrence of Crohn's Disease upon Treatment with Three Different Tumor Necrosis Factor Inhibitors.", "title_normalized": 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{ "abstract": "We present a case of severe lactic acidosis due to exacerbation of asthma in presence of normal tissue perfusion and oxygenation in a 35-year-old woman with poorly controlled asthma. After admission, she was treated continuously with inhalation of salbutamol (a beta-agonist) resulting in lactic acidosis, which was misinterpreted as treatment failure. The lactic acidosis reversed on discontinuation of the inhalation therapy. Although lactic acidosis is a rare complication to inhalation of beta-agonists, it is important for the clinicians to recognize this.", "affiliations": "Anæstesi- og operationsklinikken, Juliane Marie Centret, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark. kimekelund@gmail.com", "authors": "Ekelund\|Kim\|K\|;Følsgaard\|Søren\|S\|", "chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol", "country": "Denmark", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-5782", "issue": "175(3)", "journal": "Ugeskrift for laeger", "keywords": null, "medline_ta": "Ugeskr Laeger", "mesh_terms": "D000140:Acidosis, Lactic; D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000328:Adult; D000420:Albuterol; D001249:Asthma; D005260:Female; D006801:Humans; D009330:Nebulizers and Vaporizers; D016896:Treatment Outcome", "nlm_unique_id": "0141730", "other_id": null, "pages": "112-4", "pmc": null, "pmid": "23331939", "pubdate": "2013-01-14", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lactic acidosis in a patient with exercabation of asthma receiving inhalation therapy.", "title_normalized": "lactic acidosis in a patient with exercabation of asthma receiving inhalation therapy" }	[ { "companynumb": "PHHY2013DK044943", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IPRATROPIUM" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, 6QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPRATROPIUM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": "072151", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INHALER", "drugdosagetext": "5 MG, PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "37.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachypnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EKELUND K., FOLSGAARD S. LACTIC ACIDOSIS IN A PATIENT WITH EXERCABATION OF ASTHMA RECEIVING INHALATION THERAPY. UGESKRIFT FOR LAEGER. 2013;175 (3):112-114", "literaturereference_normalized": "lactic acidosis in a patient with exercabation of asthma receiving inhalation therapy", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20150109", "receivedate": "20130510", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9283760, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]
{ "abstract": "BACKGROUND\nAcute lymphoblastic leukemia is an invasive malignancy which ought to be treated with several cytotoxic medications. Vincristine-based regimen is among the most commonly used regimens for the treatment of adult acute lymphoblastic leukemia. Peripheral neuropathy caused by vincristine provides a limitation in dose administration and can influence the treatment outcome and patient's quality of life.\n\n\nMETHODS\nIleus and constipation occurred as a result of autonomic neuropathy in a 58-year-old man who underwent vincristine-based regimen for acute lymphoblastic leukemia treatment. Despite the administration of several laxative agents for constipation, the complication did not improve. So metoclopramide as a prokinetic agent was administered intravenously, and patient bowel movement and defecation started after 24 h.\n\n\nCONCLUSIONS\nThere is no approved protocol for vincristine-induced autonomic neuropathy treatment; thus, prokinetic agents such as metoclopramide can be considered as an option for ileus treatment after ruling out the possibility of bowel obstruction. Prophylactic stool softeners should be administrated in all patients undergoing chemotherapy with vincristine to prevent gastrointestinal motility disorders.", "affiliations": "Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Research Center for Rational Use of Drugs, and Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.", "authors": "Masoumi\|Hamidreza T\|HT\|;Hadjibabaie\|Molouk\|M\|;Zarif-Yeganeh\|Morvarid\|M\|https://orcid.org/0000-0003-2196-4119;Khajeh\|Behrouz\|B\|https://orcid.org/0000-0002-5645-4955;Ghavamzadeh\|Ardeshir\|A\|", "chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D005765:Gastrointestinal Agents; D014750:Vincristine; D008787:Metoclopramide", "country": "England", "delete": false, "doi": "10.1177/1078155217746228", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "25(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Vincristine; acute lymphoblastic leukemia; ileus; metoclopramide; neuropathy", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D003248:Constipation; D005765:Gastrointestinal Agents; D006801:Humans; D045823:Ileus; D008297:Male; D008787:Metoclopramide; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014750:Vincristine", "nlm_unique_id": "9511372", "other_id": null, "pages": "507-511", "pmc": null, "pmid": "29224457", "pubdate": "2019-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of vincristine-induced ileus with metoclopramide: A case report.", "title_normalized": "treatment of vincristine induced ileus with metoclopramide a case report" }	[ { "companynumb": "IR-CUMBERLAND PHARMACEUTICALS INC.-2063899", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LACTULOSE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "074712", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONSTIPATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KRISTALOSE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Flat affect", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MASOUMI HT, HADJIBABAIE M, ZARIF-YEGANEH M, ET AL. TREATMENT OF VINCRISTINE-INDUCED ILEUS WITH METOCLOPRAMIDE: A CASE REPORT. JOURNAL OF ONCOLOGY PHARMACY PRACTICE 2019? 25(2): 507-511.", "literaturereference_normalized": "treatment of vincristine induced ileus with metoclopramide a case report", "qualification": null, "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20190312", "receivedate": "20190312", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 16064518, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "IR-MYLANLABS-2019M1015404", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISACODYL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUPPOSITORY", "drugdosagetext": "10 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "LAXATIVE SUPPORTIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISACODYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "EVERY FOUR DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE TIMES DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": 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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "POLYETHYLENE GLYCOL 3350" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONSTIPATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MACROGOL 3350" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SENNA LEAF" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LAXATIVE SUPPORTIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SENNA /00142201/" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MAGNESIUM HYDROXIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LAXATIVE SUPPORTIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM HYDROXIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ILEUS PARALYTIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "EVERY FOUR DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONSTIPATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "POLYETHYLENE GLYCOL 3350" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FORMULATION: ENEMA", "drugenddate": null, "drugenddateformat": null, "drugindication": "ILEUS PARALYTIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MACROGOL 3350" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BISACODYL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "LAXATIVE SUPPORTIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISACODYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160-800 MG THREE TIMES PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "EVERY FOUR DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR /00587301/" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Autonomic neuropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ileus paralytic", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MASOUMI HT, HADJIBABAIE M, ZARIF-YEGANEH M, KHAJEH B, GHAVAMZADEH A. TREATMENT OF VINCRISTINE-INDUCED ILEUS WITH METOCLOPRAMIDE: A CASE REPORT. J-ONCOL-PHARM-PRACT 2019?25(2):507-511.", "literaturereference_normalized": "treatment of vincristine induced ileus with metoclopramide a case report", "qualification": "2", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20190221", "receivedate": "20190221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15990506, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.", "affiliations": "Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Pediatric Neurology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Pediatric Ophthalmology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.", "authors": "Horvath\|Gabriella-Ana\|GA\|;Hukin\|Juliette\|J\|;Stockler-Ipsiroglu\|Sylvia G\|SG\|;Aroichane\|Maryam\|M\|", "chemical_list": "D000927:Anticonvulsants; D013654:Taurine; D050644:Succinate-Semialdehyde Dehydrogenase; D020888:Vigabatrin", "country": "Germany", "delete": false, "doi": "10.1055/s-0036-1583183", "fulltext": null, "fulltext_license": null, "issn_linking": "0174-304X", "issue": "47(4)", "journal": "Neuropediatrics", "keywords": null, "medline_ta": "Neuropediatrics", "mesh_terms": "D000592:Amino Acid Metabolism, Inborn Errors; D000927:Anticonvulsants; D002648:Child; D002658:Developmental Disabilities; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D058499:Retinal Dystrophies; D050644:Succinate-Semialdehyde Dehydrogenase; D013654:Taurine; D020888:Vigabatrin", "nlm_unique_id": "8101187", "other_id": null, "pages": "263-7", "pmc": null, "pmid": "27104484", "pubdate": "2016-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.", "title_normalized": "eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency" }	[ { "companynumb": "CA-LUNDBECK-DKLU2013094", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal dystrophy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HORVATH G, HUKIN J, STOCKLER-IPSIROGLU S, AROICHANE M. EYE FINDINGS ON VIGABATRIN AND TAURINE TREATMENT IN TWO PATIENTS WITH SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY. NEUROPEDIATRICS. 2016 APR 22;.", "literaturereference_normalized": "eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20170922", "receivedate": "20170922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13999228, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "CA-LUNDBECK-DKLU1081340", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENZYME ABNORMALITY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal dystrophy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HORVATH G, HUKIN J, STOCKLER-IPSIROGLU S, AROICHANE M. EYE FINDINGS ON VIGABATRIN AND TAURINE TREATMENT IN TWO PATIENTS WITH SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY. NEUROPEDIATRICS. 2016;.", "literaturereference_normalized": "eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CA", "receiptdate": "20170925", "receivedate": "20170925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 14008803, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]
{ "abstract": "Reported here is the case of a severely disabled young girl who developed Fanconi syndrome secondary to long-term valproic acid administration, ultimately leading to hypophosphatemic rickets. Although nephrocalcinosis is not a common feature in patients with proximal tubulopathy, the patient presented also with this condition, and the concomitant use of another anticonvulsant might have potentiated this condition. The purpose of this report is to increase awareness among healthcare providers of such rare but significant complications associated with anticonvulsants.", "affiliations": "Pediatrics Department, McMaster University, Hamilton, Canada. kelau@mcmaster.ca", "authors": "Lau\|Keith K\|KK\|;Papneja\|Koyelle\|K\|", "chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2012()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000927:Anticonvulsants; D002648:Child; D003937:Diagnosis, Differential; D005198:Fanconi Syndrome; D005260:Female; D005632:Fructose; D006801:Humans; D009397:Nephrocalcinosis; D012279:Rickets; D012640:Seizures; D000077236:Topiramate; D014635:Valproic Acid", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "22665570", "pubdate": "2012-02-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15025812;18436283;16997051;19201620;11322374;21586883;21874139;20466520;19302942;20304335;17515139;7688423;7624000;12042105;21638910;8108303;21717384;20686423;17877442;6782217;11473672;15816962;20888032;11442157;12435575;16450323;15785938;3146224;15230715;3124010;12366731;12363104", "title": "Anticonvulsant-induced rickets and nephrocalcinosis.", "title_normalized": "anticonvulsant induced rickets and nephrocalcinosis" }	[ { "companynumb": "CA-IMPAX LABORATORIES, INC-2015-IPXL-00264", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "125 MG IN MORNING, 62.5 MG IN EVENING AND 125 MG IN NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX SODIUM ER" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX SODIUM ER" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARNITINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 2 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARNITINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, 2 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM CARBONATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CARBONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG IN MORNING, 12.5 MGIN EVENING AND 25 MG IN NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypophosphataemic rickets", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephrocalcinosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fanconi syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAU KK, PAPNEJA K.. ANTICONVULSANT-INDUCED RICKETS AND NEPHROCALCINOSIS. BMJ CASE REPORTS. 2012;1-4", "literaturereference_normalized": "anticonvulsant induced rickets and nephrocalcinosis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20150320", "receivedate": "20150320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10934557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "CA-RANBAXY-2013US-65561", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARNITINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARNITINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM CARBONATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CARBONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG A.M, 12.5 MG PM AND 25 MG NOCTE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091037", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125MG AM, 62.5MG PM, AND 125MG NOCTE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "11.4", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypophosphataemic rickets", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Femur fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fanconi syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephrocalcinosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypophosphataemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAU KK, PAPNEJA K. ANTICONVULSANT-INDUCED RICKETS AND NEPHROCALCINOSIS. BMJ CASE REP. 2012?FEB 25:4 PAGES", "literaturereference_normalized": "anticonvulsant induced rickets and nephrocalcinosis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151006", "receivedate": "20130305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9138302, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]
{ "abstract": "To assess the impact of the 2011 changes in pediatric single-ingredient liquid acetaminophen product packaging and standardization of the acetaminophen concentration (160 mg/5 mL) on poison control center exposures due to medication errors.\n\n\n\nNational Poison Data System (NPDS) data from January 1, 2007, through December 31, 2016, were used to identify medication error exposures involving single-ingredient liquid acetaminophen in children younger than 12 years of age. Surveys were conducted through 6 regional poison control centers to obtain additional information on a subset of exposures.\n\n\n\nThe annual frequency of NPDS exposures due to medication errors with single-ingredient liquid acetaminophen products was 8260 ± 670 exposures/year during 2007-2011. Children <2 years of age accounted for 66% of exposures. The overall rate of exposures fell to 6669 ± 662 during 2012-2016 (19% decrease; P = .005). Four percent of exposures led to health care facility referrals. Caregivers involved with exposures in children <2 years of age cited health professionals as the source of dosing information in only 69% of cases despite the absence of specific dosing directions for these children on product labels.\n\n\n\nImplementation of a single concentration for pediatric liquid acetaminophen products and packaging changes were associated with a decrease in medication errors reported to poison control centers. Medication errors are particularly problematic for children <2 years of age, for whom there are no specific labeled dosing instructions. Improved efforts to provide caregivers with dosing instructions for these children are encouraged.", "affiliations": "Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, Palos Verdes, Calif.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo. Electronic address: kate.reynolds@rmpdc.org.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo.", "authors": "Brass\|Eric P\|EP\|;Reynolds\|Kate M\|KM\|;Burnham\|Randy I\|RI\|;Green\|Jody L\|JL\|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1016/j.acap.2018.03.001", "fulltext": null, "fulltext_license": null, "issn_linking": "1876-2859", "issue": "18(5)", "journal": "Academic pediatrics", "keywords": "acetaminophen; medication error; poison prevention; regional poison control center", "medline_ta": "Acad Pediatr", "mesh_terms": "D000082:Acetaminophen; D017677:Age Distribution; D018712:Analgesics, Non-Narcotic; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D004348:Drug Labeling; D004363:Drug Utilization; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008508:Medication Errors; D019064:Product Packaging", "nlm_unique_id": "101499145", "other_id": null, "pages": "563-568", "pmc": null, "pmid": "29522886", "pubdate": "2018-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Medication Errors With Pediatric Liquid Acetaminophen After Standardization of Concentration and Packaging Improvements.", "title_normalized": "medication errors with pediatric liquid acetaminophen after standardization of concentration and packaging improvements" }	[ { "companynumb": "US-JNJFOC-20180723934", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Medication error", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BRASS EP, REYNOLDS KM, BURNHAM RI, GREEN JL. MEDICATION ERRORS WITH PEDIATRIC LIQUID ACETAMINOPHEN AFTER STANDARDIZATION OF CONCENTRATION AND PACKAGING IMPROVEMENTS. ACADEMIC PEDIATRICS JUL?2018?18 (5):563??568.", "literaturereference_normalized": "medication errors with pediatric liquid acetaminophen after standardization of concentration and packaging improvements", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180721", "receivedate": "20180721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15178005, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]
{ "abstract": "A case of a 36-year old woman with HER2-positive early breast cancer treated with adjuvant trastuzumab left ventricle dysfunction and cardiac arrest in ventricular fibrillation mechanism is presented. After having been successfully resuscitated, trastuzumab therapy was withheld, pharmacotherapy (beta-blocker, ACE-I) implemented and ICD was implanted. Echocardiography performed 6 months later, revealed normal systolic function of the left ventricle. The patient died despite further oncologic treatment due to progression of the disease. The authors discuss the approach to this dramatic but lone cardiac side effect of trastuzumab treatment.", "affiliations": "Oddział Kardiologii, Wojewódzki Szpital Specjalistyczny im. M. Kopernika, Łódź. gpiotr4@wp.pl", "authors": "Piotrowski\|Grzegorz\|G\|;Gawor\|Rafał\|R\|;Słomka\|Robert\|R\|;Banasiak\|Maciej\|M\|;Strzelecki\|Paweł\|P\|;Gawor\|Zenon\|Z\|;Potemski\|Piotr\|P\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Receptor, ErbB-2; D000068878:Trastuzumab", "country": "Poland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0022-9032", "issue": "70(7)", "journal": "Kardiologia polska", "keywords": null, "medline_ta": "Kardiol Pol", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001145:Arrhythmias, Cardiac; D001943:Breast Neoplasms; D017147:Defibrillators, Implantable; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018719:Receptor, ErbB-2; D000068878:Trastuzumab", "nlm_unique_id": "0376352", "other_id": null, "pages": "756-7", "pmc": null, "pmid": "22825957", "pubdate": "2012", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardioverter-defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type-2 breast cancer.", "title_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer" }	[ { "companynumb": "PL-MYLANLABS-2019M1112987", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLIC (4 CYCLES OF NEOADJUVANT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "761074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM/KILOGRAM, Q3W", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE, 4 CYCLES OF NEOADJUVANT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "761074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM/KILOGRAM, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE, 4 CYCLES OF NEOADJUVANT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Left ventricular dysfunction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PIOTROWSKI, G.. CARDIOVERTER-DEFIBRILLATOR IN THE TREATMENT OF ARRHYTHMIA INDUCED BY TRASTUZUMAB USED IN THE ADJUVANT SETTING IN A PATIENT WITH POSITIVE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE-2 BREAST CANCER.. POLISH CARDIOLOGY. 2012?70 (7):756-7", "literaturereference_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20191218", "receivedate": "20191218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17172176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "PL-PFIZER INC-2019263409", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/KG, CYCLIC (ADJUVANT IMMUNOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (4 CYCLES OF NEOADJUVANT AT CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/KG, CYCLIC (LOADING DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, 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POLISH CARDIOLOGY. 2012?70 (7):756-757", "literaturereference_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190814", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16474433, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "A 30-year-old Vietnamese woman, about 19 weeks pregnant, was admitted for acute cerebral infarction with stenosis of the left middle cerebral artery (LMCA), tuberculous meningitis, and miliary tuberculosis. Treatment with heparin, quadruple anti-tuberculosis therapy, and dexamethasone afforded prompt symptomatic improvement. However, she delivered a stillbirth, after which there was recurrence of acute cerebral infarction with LMCA occlusion, sinus thrombosis, and cranial base inflammation. A thrice-weekly 100 mg dose of intrathecal isoniazid (INH) improved the signs of meningeal inflammation. The patient was discharged ambulatory after 7 months. In refractory tuberculous meningitis, multimodal therapy with intrathecal INH and steroids should be considered.", "affiliations": "Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Brain and Neurosciences, Division of Neurology, Faculty of Medicine, Tottori University, Japan.", "authors": "Nakatani\|Yuko\|Y\|;Suto\|Yutaka\|Y\|;Fukuma\|Kazuki\|K\|;Yamawaki\|Mika\|M\|;Sakata\|Ryoichi\|R\|;Takahashi\|Shotaro\|S\|;Nakayasu\|Hiroyuki\|H\|;Nakashima\|Kenji\|K\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000995:Antitubercular Agents; D003907:Dexamethasone; D007538:Isoniazid", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.56.6945", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2842084610.2169/internalmedicine.56.6945Case ReportIntrathecal Isoniazid for Refractory Tuberculous Meningitis with Cerebral Infarction Nakatani Yuko 1Suto Yutaka 12Fukuma Kazuki 12Yamawaki Mika 1Sakata Ryoichi 12Takahashi Shotaro 12Nakayasu Hiroyuki 1Nakashima Kenji 21 Department of Neurology, Tottori Prefectural Central Hospital, Japan2 Department of Brain and Neurosciences, Division of Neurology, Faculty of Medicine, Tottori University, JapanCorrespondence to Dr.　Yutaka Suto, sutoyutaka.i@gmail.com\n\n15 4 2017 56 8 953 957 25 12 2015 26 7 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 30-year-old Vietnamese woman, about 19 weeks pregnant, was admitted for acute cerebral infarction with stenosis of the left middle cerebral artery (LMCA), tuberculous meningitis, and miliary tuberculosis. Treatment with heparin, quadruple anti-tuberculosis therapy, and dexamethasone afforded prompt symptomatic improvement. However, she delivered a stillbirth, after which there was recurrence of acute cerebral infarction with LMCA occlusion, sinus thrombosis, and cranial base inflammation. A thrice-weekly 100 mg dose of intrathecal isoniazid (INH) improved the signs of meningeal inflammation. The patient was discharged ambulatory after 7 months. In refractory tuberculous meningitis, multimodal therapy with intrathecal INH and steroids should be considered. \n\nintrathecal isoniazidtuberculous meningitiscerebral infarctionpregnancy\n==== Body\nIntroduction\nTuberculous meningitis is a serious disease with high rates of mortality and residual neurologic deficits (1). Although the British Infection Society has recommended treatment regimens (2), additional high-strength modalities may be needed in some serious cases. We herein report a case of tuberculous meningitis in which remission was achieved not with the recommended treatment but with intrathecal administration of isoniazid (INH).\n\nCase Report\nThe patient was a 30-year-old Vietnamese woman with no relevant medical history who was studying in Japan. She presented with common cold symptoms for 2 weeks and a fever of about 38℃, followed by right hemiplegia. These prompted consultation and subsequent admission to our hospital. The patient had undergone fertility treatment at a private obstetrics-gynecology clinic and was about 19 weeks pregnant. She had hyperemesis with a poor nutritional status, however, no weight gain during pregnancy was observed.\n\nThe general physical findings were as follows: height 157 cm, weight 52 kg, body mass index 21.1, blood pressure 116/57 mmHg, heart rate 128/min, respiration rate 30/min, body temperature 38.0℃, and oxygen saturation of 95%. There were no pertinent thoracic or abdominal findings, except for the signs of pregnancy. The neurologic findings were lucid consciousness, spontaneous pain in the posterior cervical region, nuchal rigidity, right central facial palsy, right hemiplegia (Brunnstrom stage I in the arm and fingers, Brunnstrom stage II in the leg), hyperreflexia of the right upper and lower limbs, and right leg sensory deficit. Blood inflammatory markers showed a white blood cell count of 6,920 /μL and C-reactive protein of 3.42 mg/dL. Blood biochemistry results indicated mild liver dysfunction (aspartate aminotransferase 43 IU/L, alanine aminotransferase 46 IU/L) and undernutrition, with albumin at 2.3 g/dL. There were no abnormal findings related to the kidney or pancreas function. Testing for human immunodeficiency virus was negative.\n\nThe cerebrospinal fluid (CSF) findings were as follows: pale yellow color, initial pressure 290 mmH2O, final pressure 150 mmH2O, cell count 100 /μL with a lymphocyte-to-polymorphonuclear leukocyte ratio of 67:33, protein 229 mg/dL, sugar 11 mg/dL, and positive Ziehl-Neelsen staining. Cranial magnetic resonance imaging (MRI) on diffusion-weighted images revealed acute cerebral infraction of the left putamen; magnetic resonance angiography (MRA) revealed stenosis of the left middle cerebral artery (LMCA) (Fig. 1a and b). Ground glass opacities in both lung fields were noted on chest radiograph and computed tomography (CT) (Fig. 1c and d). Cerebral infarction secondary to vasculitis from tuberculous meningitis and miliary tuberculosis were suspected.\n\nFigure 1. Radiologic imaging findings in a 30-year-old woman with refractory tuberculous meningitis. (a) Cranial MRI diffusion-weighted image shows acute cerebral infarction of the left putamen. (b) MRA shows stenosis in the horizontal segment of the left middle cerebral artery (arrow). (c) Chest radiograph shows miliary shadows in both lung fields. (d) On chest CT, there were diffuse ground glass opacities in both lung fields. MRI: magnetic resonance imaging, MRA: magnetic resonance angiography, CT: computed tomography\n\nFig. 2 shows the clinical course of the patient's hospitalization. Treatment was started with dexamethasone (19.6 mg/day) and four anti-tuberculosis drugs: INH (200 mg/day), rifampicin (RFP) (450 mg/day), ethambutol (EB) (750 mg/day), and pyrazinamide (PZA) (1.2 g/day). Because bacterial meningitis could not be ruled out, meropenem (6 g/day) was also administered. Taking into consideration the patient's pregnancy, acute cerebral infarction was treated with continuous heparin infusion at 10,000 units/day. Based on positive tubercle bacilli DNA on polymerase chain reaction and positive culture for Mycobacterium tuberculosis, the patient was given a definitive diagnosis of tuberculous meningitis. After five days of treatment, liver dysfunction ensued. When the liver dysfunction improved after a week, the administration of the four drugs was continued, with PZA being replaced by levofloxacin (LVFX) (500 mg/day). The fever and right hemiplegia promptly improved. Although Ziehl-Neelsen staining was performed only once and showed positivity and susceptibility to all anti-tuberculous drugs, the presence of Mycobacterium tuberculosis in the CSF was sustained for up to one month, despite the administration of anti-tuberculosis drugs.\n\nFigure 2. Clinical course of a 30-year-old woman with refractory tuberculous meningitis. INH: isoniazid, RFP: rifampicin, EB: ethambutol, PZA: pyrazinamide, LVFX: levofloxacin, SM: streptomycin\n\nOn hospital day 25, at 22 weeks and 1 day of gestation, the patient gave birth to a stillborn. Examination of the uterine contents revealed tubercule bacilli, confirming an intrauterine infection. After the stillbirth, the fever and meningitis signs recurred. Despite treatment with 5 anti-tuberculosis agents (with the addition of streptomycin at 1 g/day) and restarting dexamethasone administration (19.6 mg/day), no improvement in the signs of meningeal irritation was observed. On hospital day 33, aphasia and right hemiplegia appeared; on hospital day 37, right abducens nerve palsy developed. Repeat cranial MRI revealed recurrent cerebral infarction on the left parietal lobe; MRA showed peripheral occlusion of the horizontal segment of the LMCA. Findings indicative of inflammation of the cranial base and lateral sinus thrombosis were also observed (Fig. 3). These were treated with edaravone and heparin; administration of aspirin (100 mg/day) was also continued to prevent recurrence.\n\nFigure 3. Cranial MRI findings of recurrent cerebral infarction in tuberculous meningitis. (a) Diffusion-weighted images show infarcted area in the left posterior limb of the internal capsule, left corona radiata, and left parietal lobe. (b) MRA shows occlusion of the left middle cerebral artery (arrow head). (c) Enhanced T1-weighted images show inflammatory changes in the base of the brain (encircled area) and venous sinus thrombosis (arrow). MRI: magnetic resonance imaging, MRA: magnetic resonance angiography\n\nHowever, the meningitis symptoms persisted and did not improve despite increasing the INH dosage from 300 mg/day to 500 mg/day. Therefore, intrathecal administration of 100 mg of INH 3 times per week was started. Furthermore, 15 mL of CSF was intermittently drained by lumbar puncture to relieve intracranial pressure. The signs of meningeal irritation started to improve after starting intrathecal INH. Serial cranial MRI indicated resolution of the venous sinus thrombosis and reduction of the inflammatory findings in the cranial base (Fig. 4). On hospital day 98, the visual acuity on the left decreased, suggesting left optic neuritis caused by inflammation of the cranial base. As the possibility of optic neuropathy could not be ruled out, EB was discontinued. Intrathecal INH administration was tapered to once a week and eventually was discontinued as the patient's symptoms improved.\n\nFigure 4. Cranial MRI after intrathecal administration of INH for tuberculous meningitis complicated by cerebral infarction. Enhanced T1-weighted images show improvement of the inflammatory changes in the base of the brain (encircled area) and resolution of sinus thrombosis (arrow). MRI: magnetic resonance imaging, INH: isoniazid\n\nThe patient was discharged for home on hospital day 191. Three anti-tuberculosis drugs (INH, RFP, and LVFX) were continuously administered for 1 year. The residual neurologic deficits were mild aphasia, decreased visual acuity on the left side, and hypoesthesia in both legs, which was suspected to be secondary to INH. Nevertheless, the patient was able to independently engage in her activities of daily living. Cranial MRI 2 years after onset showed that the occlusion in the horizontal segment of the LMCA was unchanged; therefore, the administration of aspirin (100 mg/day) was continued to prevent the recurrence of cerebral infarction. Approximately 2.5 years later, the patient returned to her home country. She was able to walk without assistance and carry out her usual duties and activities.\n\nDiscussion\nTuberculous meningitis causes inflammatory changes in the base of the brain, leading to vasculitis, cranial polyneuritis, and obstructive hydrocephalus (3). Cerebral infarction as a complication is widely known to be associated with a poor prognosis (4).\n\nIn the present case, we referred to the recommendations of the British Infection Society (2) and administered a four-drug combination of INH, RFP, EB, and PZA. Although the guidelines for treating tuberculosis in pregnant patients state that PZA should be avoided as much as possible because its safety has not been established (5), we decided to continue PZA to save the mother's life, as this was a severe case of tuberculosis. Based on a report by Thwaites et al. (6), we also administered corticosteroids. The recommended treatment led to temporary improvement in the symptoms. However, this was a severe case of recurrent meningitis and cerebral infarction, sinus thrombosis, and cranial neuropathy, for which sustained improvement was only achieved by additional intrathecal administration of INH.\n\nThere have been only a small number of reports on the use of intrathecal INH. Marked improvement was noted in a case of refractory tuberculous meningitis after thrice-weekly intrathecal administration of 100 mg/day of INH (7). This therapy was also proven to achieve remission in a patient with tuberculous meningitis and liver dysfunction, where the oral administration of high-dose INH was not possible (8). In other reports, two patients were able to return to society without any serious residual effects after combination of intrathecal INH and steroid pulse therapy (9). These findings suggest that intrathecal administration of INH may contribute to an improved prognosis in refractory tuberculous meningitis.\n\nAfter administration, INH rapidly diffuses into the CSF and reaches peak concentrations in excess of 3 mg/L, which is over 30 times its minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis, within 4 hours (10, 11). INH is metabolized in the liver via the N-acetyltransferase 2 (NAT2), which is a polymorphic gene with enzymatic activity that can be altered by the presence of single nucleotide polymorphisms (SNPs) in its coding region (12). Three major genetically determined phenotypes are observed: rapid, intermediate, and slow acetylators (12, 13). Among Brazilian patients with tuberculosis, 72.8% were found to be fast acetylators (14). A meta-analysis showed a significant association between the slow acetylator genotype of NAT2 and antituberculosis drug-induced hepatotoxicity; significant results were also found in East Asians, South Asians, Brazilians, and Middle Eastern populations, but none in Caucasians (15). This implies that the efficacy of INH may be based on NAT2 gene polymorphism and race.\n\nIn our case, the resistance to standard tuberculous therapy and the effectiveness of intrathecal INH were probably due to 1) disturbance of CSF circulation, 2) decline in INH penetration to the focal lesion, and 3) the possibility that the patient was a rapid acetylator of NAT2, although we did not investigate the polymorphism status in the present case. Overall, these findings suggest that refractory tuberculous meningitis or tuberculous meningitis complicated by anti-tuberculosis drug-induced hepatotoxicity may be indications for treatment with intrathecal INH.\n\nThis case exhibited recurrent meningitis symptoms and required administration of corticosteroids over several months. Corticosteroids can improve CSF findings, reduce intracranial pressure, and decrease inflammation (16, 17). It has also been suggested that corticosteroids be routinely used in HIV-negative people with tuberculous meningitis to reduce the risk of death and disabling residual neurologic deﬁcit among survivors (1). Thwaites et al. (6) reported a protocol involving steroid discontinuation after 4 weeks. However, in refractory cases with persistent meningitis symptoms longer than 4 weeks, as exemplified by our patient, we believe that prolonged administration of corticosteroids can be considered.\n\nIn conclusion, multimodal therapy, including intrathecal administration of INH and systemic steroids, should be considered for cases of refractory tuberculous meningitis.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nPrasad K , Singh MB \nCorticosteroids for managing tuberculous meningitis . Cochrane Database Syst Rev \nCD002244 , 2008 .18254003 \n2. \nThwaites G , Fisher M , Hemingway C , Scott G , Solomon T , Innes J , British Infection Society \nBritish Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children . J Infect \n59 : 167 -187 , 2009 .19643501 \n3. \nDastur DK , Manghani DK , Udani PM \nPathology and pathogenetic mechanisms in neurotuberculosis . Radiol Clin North Am \n33 : 733 , 1995 .7610242 \n4. \nWasay M , Farooq S , Khowaja ZA , et al \nCerebral infarction and tuberculoma in central nervous system tuberculosis: frequency and prognostic implications . J Neurol Neurosurg Psychiatry \n85 : 1260 -1264 , 2014 .24623792 \n5. \nHamadeh MA , Glassroth J \nTuberculosis and pregnancy . Chest \n101 : 1114 -1120 , 1992 .1555428 \n6. \nThwaites GE , Nguyen DB , Nguyen HD , et al \nDexamethasone for the treatment of tuberculous meningitis in adolescents and adults . N Engl J Med \n351 : 1741 -1751 , 2004 .15496623 \n7. \nTakahashi T , Ogawa K , Sawada S , et al \nA case of refractory tuberculous meningitis markedly improved by intrathecal administration of isoniazid (INH) . Rinsho Shinkeigaku \n43 : 20 -25 , 2003 (in Japanese, Abstract in English).12820546 \n8. \nDanielides IC , Constantoulakis M , Daikos GK \nHepatitis on high dose isoniazid: reintroduction of the drug in severe tuberculous meningitis . Am J Gastroenterol \n148 : 650 -655 , 1983 .\n9. \nTakahashi I , Yamada M , Matsushima M , et al \nTreatment of intractable tuberculous meningitis using intrathecal isoniazid administration and steroid pulse therapy; a report of two cases . Rinsho Shinkeigaku \n52 : 551 -556 , 2012 (in Japanese, Abstract in English).22975852 \n10. \nThwaites GE , van Toorn R , Schoeman J \nTuberculous meningitis: more questions, still too few answers . Lancet Neurol \n12 : 999 -1010 , 2013 .23972913 \n11. \nEllard GA , Humphries MJ , Allen BW \nCerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis . Am Rev Respir Dis \n148 : 650 -655 , 1993 .8368635 \n12. \nTeixeira RL , Morato RG , Cabello PH \nGenetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients . Mem Inst Oswaldo Cruz \n106 : 716 -724 , 2011 .22012226 \n13. \nKinzig-Schippers M , Tomalik-Scharte D , Jetter A , et al \nShould we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? \nAntimicrob Agents Chemother \n49 : 1733 -1738 , 2005 .15855489 \n14. \nPossuelo LG , Castelan JA , de Brito TC , et al \nAssociation of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil . Eur J Clin Pharmacol \n64 : 673 -681 , 2008 .18421452 \n15. \nDu H , Chen X , Fang Y , et al \nSlow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis . Mol Biol Rep \n40 : 3591 -3596 , 2013 .23277397 \n16. \nFeldman S , Behar AJ , Weber D \nExperimental tuberculous meningitis in rabbits . AMA Arch Pathol \n65 : 343 -354 , 1958 .13507821 \n17. \nParsons M \nTuberculous Meningitis: Tuberculomas and Spinal Tuberculosis: A Handbook for Clinicians . Oxford: Oxford University Press , 1988 : 32 -62 .\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(8)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "cerebral infarction; intrathecal isoniazid; pregnancy; tuberculous meningitis", "medline_ta": "Intern Med", "mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000995:Antitubercular Agents; D044466:Asians; D002544:Cerebral Infarction; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D007278:Injections, Spinal; D007538:Isoniazid; D012008:Recurrence; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal; D014391:Tuberculosis, Miliary", "nlm_unique_id": "9204241", "other_id": null, "pages": "953-957", "pmc": null, "pmid": "28420846", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22975852;1555428;22012226;15496623;18254003;6859018;23277397;12820546;13507821;7610242;15855489;8368635;19643501;24623792;18421452;23972913", "title": "Intrathecal Isoniazid for Refractory Tuberculous Meningitis with Cerebral Infarction.", "title_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction" }	[ { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-143361", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "084764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Noninfective encephalitis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral artery occlusion", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intracranial venous sinus thrombosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y, SUTO Y, FUKUMA K, YAMAWAKI M, SAKATA R, TAKAHASHI S, ET AL. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. 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INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. 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"drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "19.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE SALT NOT SPECIFIED" } ], "patientagegroup": "5", "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y, SUTO Y, FUKUMA K, YAMAWAKI M, SAKATA R, TAKAHASHI S, ET AL. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE 2017?56(8):953-7", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180105", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14355699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "JP-PFIZER INC-2018010502", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": 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"1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NONINFECTIVE ENCEPHALITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078579", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078579", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 G, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "STREPTOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "STREPTOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI, Y.. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE. 2017?56:953-957", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200130", "receivedate": "20180112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14381902, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "JP-FRESENIUS KABI-FK201705281", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "19.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200674", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": "017029", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091181", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS BACTERIAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Maternal drugs affecting foetus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis tuberculous", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intracranial venous sinus thrombosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Noninfective encephalitis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral artery occlusion", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y,SUTO Y,FUKUMA K,YAMAWAKI M,SAKATA R,TAKAHASHI S,ET AL.. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE 2017;953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170623", "receivedate": "20170623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13681560, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "JP-MITSUBISHI TANABE PHARMA CORPORATION-J201326063", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "209176", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADICUT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "NAKATANI Y,SUTO Y,FUKUMA K,YAMAWAKI M,SAKATA R,TAKAHASHI S,NAKAYASU H,NAKASHIMA K. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE. 2017;56:953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170523", "receivedate": "20170518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13561771, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "JP-MYLANLABS-2017M1036683", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EDARAVONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG/DAY; LATER INCREASED TO 300MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "STREPTOMYCIN\\STREPTOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "STREPTOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300MG/DAY; LATER INCREASED TO 500MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "19.6MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG 3 TIMES /WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10000 UNITS/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual acuity reduced", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y, SUTO Y, FUKUMA K, YAMAWAKI M, SAKATA R, TAKAHASHI S, ET AL. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERN-MED 2017;56(8):953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170620", "receivedate": "20170620", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13669223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "OBJECTIVE\nTo evaluate pegylated interferon alpha2a (PegIFN-alpha2a) in Egyptian patients with HCV genotype 4, and the impact of pretreatment viral load, co-existent bilharziasis and histological liver changes on response rate.\n\n\nMETHODS\nA total of 73 naive patients (61 with history of bilharziasis) with compensated chronic HCV genotype 4 were enrolled into: group A (38 patients) who received 180 mg PegIFN-alpha2a subcutaneously once weekly for a year and group B (35 patients) received IFN alpha-2a 3 MU 3 times weekly. Ribavirin was added to each regimen at a dose of 1200 mg. Patients were followed for 72 wk and sustained response was assessed.\n\n\nRESULTS\nSignificant improvement in both end of treatment response (ETR) (P < 0.002) and sustained response (SR) (P < 0.05) was noted with pegylated interferon, where ETR was achieved in 29 (76.3%) and 14 patients (40%) in both groups respectively, and 25 patients in group A (65.8%) and 9 (25.7%) in group B could retain negative viraemia by the end of follow up period. Sustained virological response (SVR) showed a significant negative correlation with age and positive correlation with pretreatment inflammation in patients receiving PegIFN. Viral clearance after 3 mo of therapy was associated with high incidence of ETR and SR (P < 0.001), but without significant difference between both forms of interferon. Significant improvement in response was achieved in patients with high grade fibrosis (grade 3 and 4) with PegIFN-alpha2a, where SR was seen in 5 out of 13 patients in group A, but none in group B. There was no significant difference in response between bilharzial and non-bilharzial patients in both groups. In terms of safety and tolerability, neutropenia was the predominant side effect; both drugs were comparable.\n\n\nCONCLUSIONS\nPegIFN-alpha2a combined with ribavirin results in improvement in sustained response in HCV genotype 4, irrespective of history of bilharzial infestation.", "affiliations": "Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar. mod2002@qatar-med.cornell.edu", "authors": "Derbala\|M F\|MF\|;Al Kaabi\|S R\|SR\|;El Dweik\|N Z\|NZ\|;Pasic\|F\|F\|;Butt\|M T\|MT\|;Yakoob\|R\|R\|;Al-Marri\|A\|A\|;Amer\|A M\|AM\|;Morad\|N\|N\|;Bener\|A\|A\|", "chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a", "country": "United States", "delete": false, "doi": "10.3748/wjg.v12.i35.5692", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "12(35)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000328:Adult; D000818:Animals; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008099:Liver; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D012547:Schistosoma; D012552:Schistosomiasis; D016896:Treatment Outcome", "nlm_unique_id": "100883448", "other_id": null, "pages": "5692-8", "pmc": null, "pmid": "17007024", "pubdate": "2006-09-21", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": "10895435;10886538;11177692;11757747;11859276;12324553;12515909;12774014;12905138;14679330;14739104;15117320;15479353;8914006;9031902;9670833;15543591;15644127;15888797;15908318;15985008;15990196;10882578;11106716", "title": "Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.", "title_normalized": "treatment of hepatitis c virus genotype 4 with peginterferon alfa 2a impact of bilharziasis and fibrosis stage" }	[ { "companynumb": "QA-ROCHE-1450243", "fulfillexpeditecriteria": "1", "occurcountry": "QA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGINTERFERON ALFA-2A" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MU 3 TIMES WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON ALFA-2A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thyroid disorder", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DERBALA M, AL KAABI S, EL DWEIK N, PASIC F, BUTT M, YAKOOB R, AL MARRI A, AMER A, MORAD N AND BENER A. TREATMENT OF HEPATITIS C VIRUS GENOTYPE 4 WITH PEGINTERFERON ALFA-2A: IMPACT OF BILHARZIASIS AND FIBROSIS STAGE. WORLD JOURNAL OF GASTROENTEROLOGY : WJG 2006 SEP 21;12(35):5692-5698.", "literaturereference_normalized": "treatment of hepatitis c virus genotype 4 with peginterferon alfa 2a impact of bilharziasis and fibrosis stage", "qualification": "3", "reportercountry": "QA" }, "primarysourcecountry": "QA", "receiptdate": "20140819", "receivedate": "20140819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10392468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "Sevelamer is an important drug used to lower serum phosphate levels in advanced kidney disease and in patients on dialysis. This drug is generally well tolerated but some patients report mild gastrointestinal distress as a side effect. Although regulatory agencies, such as Food and Drug Administration, list bowel ischemia and necrosis as potential and rare side effects, there are few case reports describing these adverse effects. We present a 35-year-old HIV patient with end-stage renal disease on hemodialysis who developed colonic hemorrhage and perforation. Imaging showed ischemic gangrene of bowel wall. Histopathology was consistent with transmural ischemic necrosis with deposition of fibrin thrombi and sevelamer crystals.", "affiliations": "Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Internal Medicine, Primary Care, Bellin Health, Marinette, WI, USA.", "authors": "Keri\|K C\|KC\|;Veitla\|V\|V\|;Samji\|N S\|NS\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/ijn.IJN_80_18", "fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Wolters Kluwer - Medknow India IJN-29-19110.4103/ijn.IJN_80_18Case ReportIschemic Colitis in Association with Sevelamer Crystals Keri K. C. Veitla V. Samji N. S. 1Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA1 Department of Internal Medicine, Primary Care, Bellin Health, Marinette, WI, USAAddress for correspondence: Dr. K. C. Keri, Department of Medicine, Division of Nephrology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: kkeri@mcw.eduMay-Jun 2019 29 3 191 193 Copyright: © 2019 Indian Journal of Nephrology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Sevelamer is an important drug used to lower serum phosphate levels in advanced kidney disease and in patients on dialysis. This drug is generally well tolerated but some patients report mild gastrointestinal distress as a side effect. Although regulatory agencies, such as Food and Drug Administration, list bowel ischemia and necrosis as potential and rare side effects, there are few case reports describing these adverse effects. We present a 35-year-old HIV patient with end-stage renal disease on hemodialysis who developed colonic hemorrhage and perforation. Imaging showed ischemic gangrene of bowel wall. Histopathology was consistent with transmural ischemic necrosis with deposition of fibrin thrombi and sevelamer crystals.\n\nSevelamer associated bowel ischemiasevelamer associated gastrointestinal bleedingsevelamer crystals\n==== Body\nIntroduction\nSevelamer is very commonly used non-calcium-phosphate-binding agent in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients to lower blood phosphate levels.[12] It was first approved for use in 2000. Currently, it is available as sevelamer hydrochloride and sevelamer bicarbonate. Use of this medication has been increasing due to its efficacy with phosphate lowering and the proposed lack of hypercalcemia and associated vascular calcification.[3]\n\nMost commonly reported side effects of sevelamer are noted to be nausea, vomiting, constipation, flatulence, and diarrhea. Although regulatory agencies such as Food and Drug Administration and the drug label list bowel perforation and ischemia as some of the more serious adverse reactions, there is insufficient literature in support of these effects.\n\nIn this case report, we describe a 35-year-old African-American female patient who was treated with sevelamer hydrochloride who presented with acute abdominal pain caused by ischemic colitis and hemorrhage. Biopsy of the right colon tissue revealed fibrinoid necrosis and deposition of crystals, whose description was consistent with sevelamer crystals.\n\nCase Report\nThis is a 35-year African-American female patient with ESRD due to idiopathic focal segmental glomerular sclerosis on hemodialysis. Significant medical history included HIV and seizure disorder. Seizure disorder was been well controlled on phenytoin. HIV status is monitored by HIV clinics at our institution. Her recent CD4 count was within normal limits and the viral load undetectable. Maintenance medication regimen included sevelamer 4.8 g/day, calcitriol, darbepoetin, cholecalciferol, clopidogrel, abacavir, lamivudine, and phenytoin. Notably, she was on sevelamer 1600 md three times a day.\n\nOur patient presented to the hospital with hematochezia, bright red bleeding per rectum and right lower quadrant abdominal pain. At the time of presentation, BP was 114/70, temperature was 98.5°F, and heart rate was 124/min. Blood chemistries were that of an ESRD patient with potassium of 5 mg/dl, serum creatinine of 6.92 mg/dl, and BUN of 41 mg/dl. Contrast CT scan of abdomen and pelvis showed cecal and colon dilatation (15–16 cm), intraluminal hemorrhage, and fat stranding. Lack of bowel wall enhancement was suggestive of ischemic colitis. Due to the above findings, patient underwent exploratory laparotomy and right hemicolectomy which was later followed by ileocolic anastomosis.\n\nThe excised tissue was promptly subjected to pathological analysis. Histopathology of the right colonic tissue showed patchy transmural ischemic necrosis with vascular fibrin thrombi and presence of sevelamer crystals at the necrotic bed and site of perforation [Figures 1 and 2]. These crystals demonstrated broad and curved “fish scale” like morphology. The scales intersected at curved points and displayed a 2-toned pink linear accentuation against a rusty yellow background.\n\nFigure 1 Fibrinoid necrosis (H and E)\n\nFigure 2 Sevelamer crystals displaying broad and curved 2-toned fish scales\n\nDiscussion\nSevelamer is an anion exchanger free of calcium and other metals. This polymeric resin has multiple amines on a carbon backbone. Amines in the polymer exist in a protonated form in the GI tract. Due to their charge, they bind phosphate anion decreasing the overall absorption of phosphorus from the GI tract.[4]\n\nMucosal injury caused by other sequestering agents such as sodium polystyrene sulfate has been reported but little data exist on sevelamer-associated gastrointestinal injury.[567]\n\nSevelamer crystal-associated GI injury was first reported in 2008.[8] In this case report, stercoral ulceration due to fecaloma formation lead to lower intestinal bleeding. The severe constipation was attributed to sevelamer use. However, they did not report sevelamer crystal deposition on histopathology.\n\nIn 2014, Swanson et al. reported a spectrum of GI mucosal injury associated with sevelamer crystal deposition in a case series of 15 patients.[9] Also, the crystal deposition was reported in esophagus, small bowel, and colon. This series described that sevelamer crystals demonstrated broad and curved “fish scale” like morphology. The scales intersected at curved points and displayed a 2-toned pink linear accentuation against a rusty yellow background. They stained eosinophilic to brown on hematoxylin and eosin (H and E) stain and violet on periodic acid-Schiff staining with diastase. To confirm the validity of their findings, they crushed sevelamer tablets and subjected to routine H and E and PAS staining. The crystals in tables demonstrated identical crystal structure to those seen in patient specimens.\n\nSince the publication of this study, there have been reports on sevelamer-associated sigmoidal bleeding,[10] sigmoid colon perforation,[11] and GI mucosal injury causing sigmoid colon mucosal injury with bleeding.[12]\n\nIn our case, the resected bowel was subjected to routine histopathological analysis. Pathology revealed patchy transmural ischemic necrosis [Figure 1] with vascular fibrin thrombi along with sevelamer crystal deposition. The crystals on H and E stained exhibited broad and curved fish scales with two tones against a yellow-brown background. The histopathological description of these crystals is similar to what was described by Swanson et al. Possibility of kayexalate can be raised but the patient had not ingested kayexalate prior around this event. Moreover, kayexalate crystals have narrow rectangular fish scales and are usually exhibit a single color.\n\nDespite visualization of sevelamer crystals at the site of necrosis, the regular causes of bowel ischemia must always be considered. Given the duration of dialysis, vascular calcification and resultant ischemia put these patients at a very high risk of vascular events. Mesenteric ischemia due to invasive fungi throughout the gastrointestinal tract has been reported in dialysis patients.[1314] Another consideration is beta-2 microglobulin amyloidosis. This has been reported to cause ischemic insult throughout the GI tract.[15]\n\nConclusion\nAlthough a rarely described entity, the awareness that sevelamer may be associated with intestinal ischemia is important. However, one must always consider and rule out the common causes of mesenteric ischemia such as atherosclerosis and vascular calcifications along with less common conditions associated with angioinvasive fungal infections and beta-2 microglobulin amyloidosis. More studies are needed to establish if sevelamer is a mere association versus if it causes ischemic injury on its own.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Delmez J Block G Robertson J Chasan-Taber S Blair A Dillon M A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis Clin Nephrol 2007 68 386 91 18184521 \n2 Mathew S Lund RJ Strebeck F Tustison KS Geurs T Hruska KA Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy J Am Soc Nephrol 2007 18 122 30 17182886 \n3 Wang C Liu X Zhou Y Li S Chen Y Wang Y New conclusions regarding comparison of sevelamer and calcium-based phosphate binders in coronary-artery calcification for dialysis patients: A meta-analysis of randomized controlled trials PLoS One 2015 10 e0133938 26230677 \n4 Barna MM Kapoian T O’Mara NB Sevelamer carbonate Ann Pharmacother 2010 44 127 34 19955298 \n5 Lillemoe KD Romolo JL Hamilton SR Pennington LR Burdick JF Williams GM Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: Clinical and experimental support for the hypothesis Surgery 1987 101 267 72 3824154 \n6 Sterns RH Rojas M Bernstein P Chennupati S Ion-exchange resins for the treatment of hyperkalemia: Are they safe and effective? J Am Soc Nephrol 2010 21 733 5 20167700 \n7 Watson M Abbott KC Yuan CM Damned if you do, damned if you don’t: Potassium binding resins in hyperkalemia Clin J Am Soc Nephrol 2010 5 1723 6 20798253 \n8 Madan P Bhayana S Chandra P Hughes JI Lower gastrointestinal bleeding: Association with sevelamer use World J Gastroenterol 2008 14 2615 6 18442219 \n9 Swanson BJ Limketkai BN Liu TC Montgomery E Nazari K Park JY Sevelamer crystals in the gastrointestinal tract (GIT): A new entity associated with mucosal injury Am J Surg Pathol 2013 37 1686 93 24061514 \n10 Subramanian CR GI mucosal injury and bleeding: Association with sevelamer crystals J Gastrointest Dig Syst 2016 12 346 7 \n11 Yamaguchi T Ohyama S Furukawa H Sato N Ohnishi I Kasashima S Sigmoid colon diverticula perforation associated with sevelamer hydrochloride administration: A case report Ann Med Surg (Lond) 2016 10 57 60 27547398 \n12 Chintamaneni P Das R Kuan SF Kermanshahi TR Hashash JG Hematochezia associated with sevalamer-induced mucosal injury ACG Case Rep J 2014 1 145 7 26157856 \n13 Chaudhary A Jain V Dwivedi RS Misra S Invasive aspergillosis causing small bowel infarction in a patient of carcinoma breast undergoing chemotherapy J Carcinog 2006 5 18 16753069 \n14 Lee ZJ Chia C Busmani I Wong WK A rare cause of ischemic gut: A case report Int J Surg Case Rep 2016 20 114 7 26852360 \n15 Dulgheru EC Balos LL Baer AN Gastrointestinal complications of beta2-microglobulin amyloidosis: A case report and review of the literature Arthritis Rheum 2005 53 142 5 15696571\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0971-4065", "issue": "29(3)", "journal": "Indian journal of nephrology", "keywords": "Sevelamer associated bowel ischemia; sevelamer associated gastrointestinal bleeding; sevelamer crystals", "medline_ta": "Indian J Nephrol", "mesh_terms": null, "nlm_unique_id": "8914356", "other_id": null, "pages": "191-193", "pmc": null, "pmid": "31142966", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "15696571;16753069;17182886;18184521;18442219;19955298;20167700;20798253;24061514;26157856;26230677;26852360;27547398;3824154", "title": "Ischemic Colitis in Association with Sevelamer Crystals.", "title_normalized": "ischemic colitis in association with sevelamer crystals" }	[ { "companynumb": "US-SA-2018SA111164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"5", "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Crystal deposit intestine", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain lower", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematochezia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI KC, VEITLA V, SAMJI NS.. 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"065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rectal haemorrhage", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematochezia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain lower", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI K, VEITLA V, BAL N, PANT M. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. AMERICAN JOURNAL OF KIDNEY DISEASES. 2018?71(4):554", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190614", "receivedate": "20180501", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14834635, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0098579", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SEVELAMER CARBONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206094", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVELAMER CARBONATE TABLETS, 800 MG" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematochezia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Large intestine perforation", "reactionmeddraversionpt": "21.0", "reactionoutcome": null }, { "reactionmeddrapt": "Abdominal pain lower", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI K, VEITLA V, BAL N, PANT M. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. AM J KIDNEY DIS. 2018?71(4):554.", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180507", "receivedate": "20180507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14852835, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2019GMK041653", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SEVELAMER HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204724", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1600 MG, TID (4.8 G/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1600", "drugstructuredosageunit": "003", 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"activesubstancename": "CALCITRIOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCITRIOL." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Large intestinal haemorrhage", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Large intestine perforation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI KC, VEITLA V, SAMJI NS. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS.. INDIAN JOURNAL OF NEPHROLOGY. 2019?29(3):191-193", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190626", "receivedate": "20190614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16431013, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-ARBOR PHARMACEUTICALS, LLC-US-2019ARB001276", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CALCIUM CARBONATE\\ERGOCALCIFEROL\\RETINOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCITROL /00508501/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SEVELAMER CARBONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204451", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1600 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVELAMER CARBONATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DARBEPOETIN ALFA" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ABACAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABACAVIR." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI KC, VEITLA V, SAMJI NS. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. INDIAN J NEPHROL. 2019?29(3):191-193", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190821", "receivedate": "20190821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16726793, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "Association between thymoma and pure red cell aplasia is already well-documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.", "affiliations": "Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.", "authors": "Dragani\|Matteo\|M\|https://orcid.org/0000-0002-5754-4856;Andreani\|Giacomo\|G\|https://orcid.org/0000-0003-4877-3929;Familiari\|Ubaldo\|U\|;Marci\|Valerio\|V\|;Rege-Cambrin\|Giovanna\|G\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2642", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2642\nCCR32642\nCase Report\nCase Reports\nPure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory\nDRAGANI et al.Dragani Matteo https://orcid.org/0000-0002-5754-4856\n1\nmatteo.dragani@gmail.com Andreani Giacomo https://orcid.org/0000-0003-4877-3929\n1\n Familiari Ubaldo \n1\n Marci Valerio \n1\n Rege‐Cambrin Giovanna \n1\n \n1 \nAzienda Ospedaliero Universitaria San Luigi Gonzaga\nUniversità di Torino\nOrbassano\nItaly\n\n* Correspondence\n\nMatteo Dragani, Hematology Department, San Luigi Gonzaga Hospital, University of Turin, Orbassano 10123, Italy.\n\nEmail: matteo.dragani@gmail.com\n\n17 3 2020 \n4 2020 \n8 4 10.1002/ccr3.v8.4598 601\n22 4 2019 09 10 2019 10 10 2019 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAssociation between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.\n\nAssociation between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.\n\n\namegakaryocytic thrombocytopeniaaplasiaeltrombopagT‐cell immunitythymoma source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:08.04.2020\n\n\nDragani \nM \n, \nAndreani \nG \n, \nFamiliari \nU \n, \nMarci \nV \n, \nRege‐Cambrin \nG \n. Pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory\n. Clin Case Rep . 2020 ;8 :598 –601\n. 10.1002/ccr3.2642\n==== Body\n1 CASE PRESENTATION\nA 62‐year‐old male was first diagnosed with lymphocyte‐rich thymoma in 2014 after being admitted in the emergency ward for sudden dyspnea and deep vein thrombosis of the right arm. His past medical history was uneventful, and he was nonsmoker. Notably, his blood examinations were perfectly normal. In June 2014, he was administered five cycles of chemotherapy based on standard CAPP (cisplatin, doxorubicin, cyclophosphamide, and prednisone) regimen obtaining a partial response.\n\nFrom 2014 to 2017, the disease remained stable; in May 2017, the tumor burden increased with enlargement of the main mediastinal lesion and metastasis localized to the pleura, the diaphragm, and the second rib. In June 2017, the oncologist picked the CAPP regimen for a rechallenge but only one course of chemo was administered due to the appearance of normocytic anemia (Hb, 7 g/dL). At first, erythropoietin was prescribed but it did not show any effect.\n\nThe patient was refereed to our hematology department for further investigation. His anemia was not carential, not due to blood loss, not hemolytic, so prescription of erythropoiesis‐stimulating factor to contain chemotherapy‐induced anemia can be of help. Differential diagnosis includes performing a bone marrow biopsy to exclude therapy‐related myelodysplasia which can impair blood count recovery and led to aggressive forms of acute myeloid leukemia.\n\nIn July 2017, while the patient already has been put under blood transfusion weekly, a bone marrow biopsy was done, and it showed pure red cell aplasia (PRCA) with normal granulocyte maturation and megakaryocytes representation and a global cellularity around 50%. No cytogenetic abnormalities associated with myelodysplasia could be detected with FISH analysis, and remarkably no sign of thymoma metastasis in the marrow had been noticed. Blood count was as follows: WBC, 5900/μL; Hb, 6.5 g/dL; and platelets 327 000/μL.\n\nThymoma is the most common neoplastic lesion of the anterior mediastinum whose paraneoplastic complications such as myasthenia gravis (MG) and pure red cell aplasia (PRCA) are well‐known. About 25%‐30% of patients with thymoma experiences MG whereas approximately 2%‐5% of thymoma patients have pure red cell aplasia1 with the possibility of achieving complete remission of the latter after cyclosporine‐based immunosuppressive therapy, especially if total thymectomy is performed.\n\nIn August 2017, the patient developed severe thrombocytopenia with mucocutaneous bleeding (platelets: 14 000/μL). A second bone marrow biopsy was done exactly one month after the first one, and it showed pure red aplasia with amegakaryocytic thrombocytopenia (Figure 1). Cellularity was about 30% with normal granulocyte representation. Notably, no myeloid blasts were detected; WT1 rate was 20 and cytogenetic testing showed no abnormalities.\n\nFigure 1 Bone marrow in July 2017 with absence of erythroid precursors, normal granulocytic, and megakaryocytic representation, cellularity around 50% (left); bone marrow in August 2017 with absence of both erythroid and megakaryocytic precursors, cellularity around 30% (right)\n\nThe development of severe thrombocytopenia just one month after the first biopsy where megakaryopoiesis showed no sign of impairment was unexpected. Patients with thymoma can experience thrombocytopenia in the context of aplastic anemia or immune thrombocytopenic purpura; in this case, aplastic anemia was ruled out due to the presence of 30% of cellularity with no sign of granulocytes’ alterations; immune thrombocytopenic purpura was excluded because it is associated with normal or increased megakaryocytes as a compensatory mechanism.\n\nAfter August 2017, the patient was both red blood cell and platelets transfusion‐dependent. Combination therapy with cyclosporine 3 mg/kg, prednisone 50 mg/die, and dose‐escalation eltrombopag until the maximum dosage of 150 mg/die was promptly initiated with the addition of deferasirox as iron chelator. Four months of this combination therapy, from October 2017 to January 2018, did not provide any benefit.\n\nThe idea behind this therapy was that this step‐by‐step cytopenia could benefit by the combination of immunosuppression with a stimulating agent like eltrombopag, plus the addition of deferasirox which in some hematological malignancies has been able to cause erythroid response.2 Complete resection of the tumor was ruled out because of the metastasis and lack of a clear cleavage plan of the main lesion. Another course of chemotherapy was taken into consideration but excluded at the end to not further impair patient's performance status and to not risk pancytopenia and neutropenic fever.\n\nAt the end of January, for the first time a neutrophil count < 1.000/uL was observed. During these months of immunosuppressive therapy, thymoma remained stable but the patient was admitted twice in the emergency ward for sepsis. When the PRCA plus AT progressed to overt severe aplastic anemia, we interrupted eltrombopag and admitted the patients into the intensive hematological care unit to try a course of horse antithymocyte globulin (ATG) plus cyclosporine and high dose of steroids. Bone marrow transplantation from matched unrelated donor was taken into consideration as a salvage plan if the blood count would have shown no response to T‐lymphocyte depletion. Unfortunately, the patient died just before the ATG administration for a massive intracranial hemorrhage, despite multiple platelet transfusions and careful management of his blood pressure.\n\n2 DISCUSSION\nOnly six patients have been reported in literature to have thymoma associated with pure red cell aplasia and amegakaryocytic thrombocytopenia (Table 1) with, as shown, different bone marrow characteristics and experiencing different oncologic management, from complete resection at first to standard chemotherapy (which includes cyclophosphamide, cisplatin, steroids, and doxorubicin).\n\nTable 1 Case reports available on PubMed\n\nReports\tSex/Age\tBM Evaluation\tPRCA—AT timeline\tThymoma history\t\nMaslovsky (2005)\tM, 41 y\tPure red cell aplasia, absence of megakaryocytes, normal maturation and differentiation of myeloid precursors\tPRCA first followed by AT after 3 mo\tThymoma diagnosed with PRCA; AT occurred after partial tumor resection and chemo.\t\nSimkins (2017)\tF, 61 y\tBM cellularity 40%, erythroid and megakaryocytic aplasia with left‐shifted myeloid maturation\tPRCA and AT at the same time\tLymphocyte‐rich thymoma, CAPP chemotherapy, radical thymectomy performed before PRCA and AT\t\nDahal (2018)\tM, 60 y\tBM hypercellular with severely depleted megakaryocytes and erythroid precursor cells and relative myeloid hyperplasia\tPRCA and AT at the same time\tRecurrent invasive thymoma, no surgery ever performed, diagnosis made before PRCA and AT\t\nOnuki (2016)\tF, 67 y\tBM hypoplastic, decreased erythroid cells, scarce megakaryocytes, adequate number of myeloid cells\tPRCA and AT at the same time\tThymoma occurred at presentation with PRCA and AT\t\nGay (2014)\tM, 31 y\tBM cellularity 20%, erythroid precursors 1%, markedly reduced to absent megakaryocytes\tPRCA and AT at the same time\tRelapsed thymoma after complete resection; PRCA and AT diagnosed after CAPP chemotherapy and partial remission\t\nFujiwara (2015)\tF, 44 y\tBM hypocellular with marked decrease in megakaryocytes and reticulocytes\tPRCA first followed by AT (no time frame available)\tRefractory thymoma diagnosed with PRCA, AT occurred after CAPP‐like chemotherapy and II line treatment with CAMP regimen\t\nPresent case (2018)\tM, 62 y\tBM cellularity 30%, normal granulocyte maturation, no evidence of erythroid and megakaryocytic precursors\tPRCA first followed by AT after 1 mo\tRefractory thymoma; no surgery ever performed; PRCA and then AT occurred after chemotherapy (first CAPP course, then rechallenge two years later).\t\nFeatures of bone marrow, time frame of PRCA (pure red cell aplasia) and AT (amegakaryocytic thrombocytopenia) occurrence, and history of thymoma are shown.\n\nJohn Wiley & Sons, LtdTreatment in this series of patient always included cyclosporine backbone, alone or in combination with prednisone, and in two cases also horse ATG were administered. Eltrombopag has been used, beside our patient, in only one case but no improvement of platelet count was obtained; at the end a bone marrow, transplant from matched unrelated donor was successfully performed.3 Our case is an example where the addition of a TPO agonist did not provide an hematological recovery, whereas in the latest years this molecule has been proven effective in the treatment of severe aplastic anemia (SAA) both as a single agent in SAA refractory to IST or in frontline combination with cyclosporine/horse ATG.4, 5\n\n\nBetween these cases, four patients were able to improve their cytopenias6, 7, 8, 9 whereas in the remaining two cases information about follow‐up were not available and one patient left the hospital few days after therapy initiation.9, 10 Notably, in three cases including ours PRCA and amegakaryocytic thrombocytopenia (AT) progressed to aplastic anemia despite immunosuppression, thus empowering the theory, previously cited in the other reports, that PRCA and AT may be early presentation of complete aplasia.\n\nOur impression is that patients with PRCA and AT with thymoma have better chances to achieve hematological improvement of their cytopenias if complete resection of the tumor can be performed at some point. Previous experiences indicate that both humoral and T cell–mediated immunity can be accounted as culprits of megakaryocytes suppression, and since thymomas can dysregulate both pathways we may assume that the presence of the tumor can overcome the effects of immunosuppressive therapy.11, 12 Nevertheless, certainties in this particular field are very scarce since thymoma itself is a rare entity and the discussion can only rely on sporadic experiences: further reports are needed as well as prospective studies to determine the role of eltrombopag, bone marrow transplantation, and surgical resection of the tumor.\n\nCONFLICTS OF INTEREST\nThe authors declare no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\nMD, GRC, and GA: treated the patient. VM and UF performed the histological analysis. MD, GRC, and GA: wrote the paper.\n==== Refs\nREFERENCES\n1 \n\nChintakuntlawar \nAV \n, \nRizvi \nSA \n, \nCassivi \nSD \n, \nPardanani \nA \n. 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Thymoma complicated by acquired amegakaryocytic thrombocytopenia and pure red cell aplasia\n. J Natl Compr Canc Netw . 2014 ;12 (11 ):1505 ‐1509\n.25361796 \n10 \n\nDahal \nS \n, \nSharma \nE \n, \nDahal \nS \n, \nShrestha \nB \n, \nBhattarai \nB \n. al ‐ Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia in thymoma\n. Case Rep Hematol . 2018 ;2018 :1 ‐3\n.\n11 \n\nBenedetti \nF \n, \nde Sabata \nD \n, \nPerona \nG \n. T suppressor activated lymphocytes (CD8+/DR+) inhibit megakaryocyte progenitor cell differentiation in a case of acquired amegakaryocytic thrombocytopenic purpura\n. Stem Cells . 1994 ;12 (2 ):205 ‐213\n.8199563 \n12 \n\nKuwaki \nT \n, \nHagiwara \nT \n, \nKato \nT \n, \nMiyazaki \nH \n. Auto antibodies neutralizing thrombopoietin in a patient with amegakaryocytic thrombocytopenic purpura\n. Blood . 2000 ;95 (6 ):2187 ‐2188\n.10755821\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(4)", "journal": "Clinical case reports", "keywords": "T‐cell immunity; amegakaryocytic thrombocytopenia; aplasia; eltrombopag; thymoma", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "598-601", "pmc": null, "pmid": "32274018", "pubdate": "2020-04", "publication_types": "D002363:Case Reports", "references": "29409729;28423296;28053696;10755821;29713553;30425070;25361796;25555981;25315166;8199563;16275552", "title": "Pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory.", "title_normalized": "pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma the uncharted territory" }	[ { "companynumb": "IT-HIKMA PHARMACEUTICALS USA INC.-IT-H14001-20-51295", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "062975", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Normocytic anaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201706" } }, "primarysource": { "literaturereference": "DRAGANI M, ANDREANI G, FAMILIARI U, MARCI V, REGE-CAMBRIN G. 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EVENT DATE: 201708" } }, "primarysource": { "literaturereference": "DRAGANI M, ANDREANI G, FAMILIARI U, MARCI V, REGE-CAMBRIN G. PURE RED CELL APLASIA AND AMEGAKARYOCYTIC THROMBOCYTOPENIA IN THYMOMA: THE UNCHARTED TERRITORY. CLINICAL CASE REPORTS. 2020?8(4):598-601.", "literaturereference_normalized": "pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma the uncharted territory", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200601", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17768411, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "IT-PFIZER INC-2020177713", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2017", "drugenddateformat": "602", "drugindication": "THYMOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201706" } }, "primarysource": { "literaturereference": "DRAGANI, M.. PURE RED CELL APLASIA AND AMEGAKARYOCYTIC THROMBOCYTOPENIA IN THYMOMA: THE UNCHARTED TERRITORY. CLINICAL CASE REPORTS. 2020?8(4):598-601", "literaturereference_normalized": "pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma the uncharted territory", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200508", "receivedate": "20200506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17750851, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]
{ "abstract": "Neurotoxic manifestations due to chronic metronidazole intake are well known, but neurotoxicity due to short-term use of metronidazole is very rare. We present a case of acute neurotoxicity due to short course of injectable metronidazole given in usual doses to a renal allograft recipient for persistent diarrhea. It responded to withdrawal of the offending drug. Tacrolimus trough concentration did not increase during neurotoxicity, thereby ruling out any metronidazole-tacrolimus interaction. Magnetic resonance imaging of the brain showed widespread osmotic demyelination and its recovery after drug withdrawal. This is the first reported case of a renal transplant recipient developing acute neurotoxicity due to short-term use of metronidazole, without any increase in tacrolimus trough concentrations.", "affiliations": "Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.", "authors": "Dogra\|Pavitra Manu\|PM\|;Bhatt\|Anil Kumar\|AK\|;Agarwal\|Sanjay Kumar\|SK\|;Bhowmik\|Dipankar\|D\|", "chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D008795:Metronidazole; D016559:Tacrolimus", "country": "Saudi Arabia", "delete": false, "doi": "10.4103/1319-2442.248315", "fulltext": null, "fulltext_license": null, "issn_linking": "1319-2442", "issue": "29(6)", "journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia", "keywords": null, "medline_ta": "Saudi J Kidney Dis Transpl", "mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D003967:Diarrhea; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008795:Metronidazole; D017590:Myelinolysis, Central Pontine; D016559:Tacrolimus; D016896:Treatment Outcome", "nlm_unique_id": "9436968", "other_id": null, "pages": "1511-1514", "pmc": null, "pmid": "30588989", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": null, "title": "Short-course metronidazole-induced reversible acute neurotoxicity in a renal transplant recipient.", "title_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient" }	[ { "companynumb": 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"activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": 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SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. 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"medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE SODIUM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "203458", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIARRHOEA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA P, BHATT A, AGARWAL S, BHOWMIK D. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. SAUDI J KIDNEY DIS TRANSPL. 2018 NOV 01?29(6):1511-4.", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190202", "receivedate": "20190202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15903287, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "IN-ACCORD-100755", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "4", "drugcumulativedosageunit": "002", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Osmotic demyelination syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. SAUDI J KIDNEY DIS TRANSPL. 2018 NOV-DEC?29(6):1511-1514.", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20191122", "receivedate": "20191122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17063189, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "IN-STRIDES ARCOLAB LIMITED-2019SP000082", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90687", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIARRHOEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebellar ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Clumsiness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Extensor plantar response", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Movement disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Speech disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D.. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT.. SAUDI-J-KIDNEY-DIS-TRANSPL. 2018?29(6):1511-1514", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15797050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "IN-GLENMARK PHARMACEUTICALS-2019GMK044380", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE SODIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2 G, BID (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "4", "drugcumulativedosageunit": "002", "drugdosageform": null, "drugdosagetext": "500 MG, TID (EVERY 8 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osmotic demyelination syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D.. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT.. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION: AN OFFICIAL PUBLICATION OF. 2018?29(6):1511-1514", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20191125", "receivedate": "20191125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17070383, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "There is limited information about the prevalence and treatment of concurrent acetaminophen and iron overdose. One case study has suggested that this combination may be lethal. We present a case of fatal intentional acetaminophen and iron overdose and treatment with extracorporeal methods, including continuous venovenous hemofiltration and plasmapheresis, for removal of both toxins.", "affiliations": "Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, USA.;Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, USA.", "authors": "Nye\|Rebecca\|R\|;Singh\|Tripti\|T\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000517231", "fulltext": null, "fulltext_license": null, "issn_linking": "0253-5068", "issue": null, "journal": "Blood purification", "keywords": "Acetaminophen; Continuous renal replacement therapy; Iron; Overdose; Plasmapheresis", "medline_ta": "Blood Purif", "mesh_terms": null, "nlm_unique_id": "8402040", "other_id": null, "pages": "1-4", "pmc": null, "pmid": "34237719", "pubdate": "2021-07-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Use of CRRT and Plasmapheresis to Treat Simultaneous Iron and Acetaminophen Overdose.", "title_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose" }	[ { "companynumb": "US-MLMSERVICE-20210811-3046446-1", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": "207229", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "100", "drugcumulativedosageunit": "032", "drugdosageform": "Tablet", "drugdosagetext": "100 DOSAGE FORM (1 TOTAL)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "325", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": "325 MILLIGRAM (TOTAL)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "325", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS SULFATE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Nye R, Singh T.. Use of CRRT and Plasmapheresis to Treat Simultaneous Iron and Acetaminophen Overdose.. Blood Purification.. 2021", "literaturereference_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220217", "receivedate": "20210902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19777404, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0130968", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETYLCYSTEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLCYSTEINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEFEROXAMINE MESYLATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076806", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INTENTIONAL OVERDOSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEFEROXAMINE MESYLATE." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NYE R, SINGH T. USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIF. 2021?8:UNK?UNK. DOI:10.1159/000517231", "literaturereference_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210903", "receivedate": "20210112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18727938, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-VISTAPHARM, INC.-VER202108-001816", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTENTIONAL OVERDOSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\HYDROCODONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "200343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTENTIONAL OVERDOSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCODONE AND ACETAMINOPHEN" } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH T, NYE R. USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIF. 2021?1?4. 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USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. 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null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VASOPRESSIN." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastric haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH T. USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIFICATION. 2021 JUL 08?.", "literaturereference_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210916", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19816181, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty-four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].", "affiliations": "Children's Healthcare of Atlanta, Atlanta, GA, USA.;University of North Carolina Health Care, Chapel Hill, NC, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Pediatric Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.", "authors": "Bernardo\|Valeria\|V\|0000-0003-4338-1184;Miles\|Alyssa\|A\|;Fernandez\|Alfred J\|AJ\|;Liverman\|Rochelle\|R\|;Tippett\|Ashley\|A\|;Yildirim\|Inci\|I\|0000-0002-8631-0020", "chemical_list": "D000935:Antifungal Agents; D003692:Delayed-Action Preparations; D013607:Tablets; D014230:Triazoles; C101425:posaconazole", "country": "Denmark", "delete": false, "doi": "10.1111/petr.13777", "fulltext": null, "fulltext_license": null, "issn_linking": "1397-3142", "issue": "24(6)", "journal": "Pediatric transplantation", "keywords": "fungal infection; pediatrics; posaconazole; therapeutic level", "medline_ta": "Pediatr Transplant", "mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000935:Antifungal Agents; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D016867:Immunocompromised Host; D007262:Infusions, Intravenous; D000072742:Invasive Fungal Infections; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D013607:Tablets; D016896:Treatment Outcome; D014230:Triazoles; D055815:Young Adult", "nlm_unique_id": "9802574", "other_id": null, "pages": "e13777", "pmc": null, "pmid": "32639095", "pubdate": "2020-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.", "title_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole" }	[ { "companynumb": "US-009507513-2008USA004667", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "4.2 MG/KG/DAY, 300 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUNGAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": null, "patientweight": "71.9", "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERNARDO V, MILES A, FERNANDEZ AJ, LIVERMAN R, TIPPETT A, YILDIRIM I. INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. PEDIATR TRANSPLANT. 2020", "literaturereference_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143817, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-009507513-2008USA004663", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "9.9 MG/KG/DAY, 200 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUNGAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "14.7 MG/KG/DAY, AFTER ADJUSTMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": null, "patientweight": "20.3", "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERNARDO V, MILES A, FERNANDEZ AJ, LIVERMAN R, TIPPETT A, YILDIRIM I. INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED-RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. PEDIATR TRANSPLANT. 2020", "literaturereference_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143735, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-009507513-2008USA004664", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "205596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSPENSION FOR INJECTION", "drugdosagetext": "9.5 MG/KG/DAY, 250 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUNGAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": null, "patientweight": "26.2", "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERNARDO V, MILES A, FERNANDEZ AJ, LIVERMAN R, TIPPETT A, YILDIRIM I. INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. PEDIATR TRANSPLANT. 2020", "literaturereference_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143721, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-009507513-2008USA004660", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "6.9 MG/KG/DAY, 300 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205053", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "9.2 MG/KG/DAY, AFTER ADJUSTMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOXAFIL" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": null, "patientweight": "43.6", "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERNARDO V, MILES A, FERNANDEZ AJ, LIVERMAN R, TIPPETT A, YILDIRIM I. INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. PEDIATR TRANSPLANT. 2020", "literaturereference_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18143631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "Immunotherapy has been in use for the treatment of melanoma since a very long time, but only recently have the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab and programmed cell death-1 inhibitors such as nivolimumab and pembrolizumab been shown to induce marked improvements in survival in patients with metastatic melanoma. An important concern arises in terms of the safety of the use of these agents in patients with autoimmune diseases, solid organ transplant recipients on immunosuppression, patients with a history of previous hepatitis B or C, and patients with HIV infections as these patients were excluded from pivotal immunotherapy studies. Here, we report on the safety and efficacy of pembrolizumab in a melanoma patient with multiple medical problems including poorly controlled rheumatoid arthritis and we review the available literature on the use of immunotherapy and autoimmune diseases. The weight of evidence suggests that these patients should be offered the opportunity to benefit from immune check point inhibitors, with drugs targeting programmed cell death-1 being preferred. More research is required to study the long-term effects of immunotherapy on patients with autoimmune diseases.", "affiliations": "aDepartment of Internal Medicine, Banner University Medical Center, Phoenix bDepartment of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, Arizona.", "authors": "Puri\|Akshjot\|A\|;Homsi\|Jade\|J\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab", "country": "England", "delete": false, "doi": "10.1097/CMR.0000000000000387", "fulltext": null, "fulltext_license": null, "issn_linking": "0960-8931", "issue": "27(5)", "journal": "Melanoma research", "keywords": null, "medline_ta": "Melanoma Res", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma; D012878:Skin Neoplasms", "nlm_unique_id": "9109623", "other_id": null, "pages": "519-523", "pmc": null, "pmid": "28817445", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis.", "title_normalized": "the safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis" }	[ { "companynumb": "US-ROCHE-2128106", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOCILIZUMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "125276", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOCILIZUMAB." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PURI A, HOMSI J. THE SAFETY OF PEMBROLIZUMAB IN METASTATIC MELANOMA AND RHEUMATOID ARTHRITIS.. MELANOMA RESEARCH 2017?27 (5):519-523.", "literaturereference_normalized": "the safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180528", "receivedate": "20180528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14942642, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "PHHY2018US008302", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201502", "drugenddateformat": "610", "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary fibrosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PURI A, HOMSI J. THE SAFETY OF PEMBROLIZUMAB IN METASTATIC MELANOMA AND RHEUMATOID ARTHRITIS.. MELANOMA RESEARCH. 2017?27(5):519-23", "literaturereference_normalized": "the safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180601", "receivedate": "20180601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14964871, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "The number of cases of coronavirus disease 2019 (COVID-19) has been exponentially increasing everyday. It is important to recognize the comorbidities and risk factors associated with this highly contagious and serious disease that has caused thousands of deaths worldwide. Patients with certain conditions like diabetes, hypertension, cardiovascular disease and chronic lung diseases have been reported to develop serious complications from COVID-19. Idiopathic pulmonary fibrosis (IPF) is a disease that is more prevalent in the elderly population, the same group that are more susceptible to serious complications from COVID-19. Our literature search did not reveal any review about COVID-19 in IPF patients. We report a patient with IPF who was exposed to COVID-19 from her spouse and died from its complications. This case would help to raise the awareness among IPF patients to follow the necessary precautions to reduce the risk of contracting the disease.", "affiliations": "Pulmonary Critical Care, Novant Health, Winston-Salem, USA.;Pulmonary Critical Care, Yale New Haven Health at Bridgeport Hospital, Bridgeport, USA.;Hematology and Oncology, Decatur Memorial Hospital, Decatur, USA.;Cardiology, Decatur Memorial Hospital, Decatur, USA.", "authors": "Rajasurya\|Venkat\|V\|;Gunasekaran\|Kulothungan\|K\|;Damarla\|Vijay\|V\|;Kolluru\|Anuradha\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.8432", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8432\nInternal Medicine\nInfectious Disease\nPulmonology\nA Fatal Case of Coronavirus Disease 2019 (COVID-19) in a Patient With Idiopathic Pulmonary Fibrosis\nMuacevic Alexander Adler John R Rajasurya Venkat 1 Gunasekaran Kulothungan 2 Damarla Vijay 3 Kolluru Anuradha 4 \n1 \nPulmonary Critical Care, Novant Health, Winston-Salem, USA \n\n2 \nPulmonary Critical Care, Yale New Haven Health at Bridgeport Hospital, Bridgeport, USA \n\n3 \nHematology and Oncology, Decatur Memorial Hospital, Decatur, USA \n\n4 \nCardiology, Decatur Memorial Hospital, Decatur, USA \n\nVenkat Rajasurya vrajasurya@gmail.com\n3 6 2020 \n6 2020 \n12 6 e843218 5 2020 3 6 2020 Copyright © 2020, Rajasurya et al.2020Rajasurya et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/33449-a-fatal-case-of-coronavirus-disease-2019-covid-19-in-a-patient-with-idiopathic-pulmonary-fibrosisThe number of cases of coronavirus disease 2019 (COVID-19) has been exponentially increasing everyday. It is important to recognize the comorbidities and risk factors associated with this highly contagious and serious disease that has caused thousands of deaths worldwide. Patients with certain conditions like diabetes, hypertension, cardiovascular disease and chronic lung diseases have been reported to develop serious complications from COVID-19. Idiopathic pulmonary fibrosis (IPF) is a disease that is more prevalent in the elderly population, the same group that are more susceptible to serious complications from COVID-19. Our literature search did not reveal any review about COVID-19 in IPF patients. We report a patient with IPF who was exposed to COVID-19 from her spouse and died from its complications. This case would help to raise the awareness among IPF patients to follow the necessary precautions to reduce the risk of contracting the disease.\n\ncovid-19corona virusipfidiopathic pulmonary fibrosisacute hypoxemic respiratory failureThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nCoronavirus disease 2019 (COVID-19) is a rapidly spreading infectious disease caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1]. This pandemic has already led to thousands of deaths worldwide, and the number of infected cases continues to rise everyday. Although this virus could infect anyone, it has been found that patients who are older and those with certain pre-existing comorbidities suffer from serious complications due to this disease. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown etiology and its prevalence is higher in the elderly population. Chronic lung disease has been recognized as a risk factor for serious COVID-19 disease, and we report a case of fatal COVID-19 viral pneumonia in a patient with IPF [1-3]. \n\nCase presentation\nOn April 2, 2020, a 79-year-old female with a history of hypertension and IPF presented with cough, worsening dyspnea, increased oxygen requirements, fever and diarrhea. Her vital signs include a temperature of 100.4°F, a heart rate of 98 bpm, an oxygen saturation of 85% on room air and a blood pressure of 102/56 mmHg. She is usually on oxygen two liters per minute at home for chronic hypoxic respiratory failure from IPF. She was on nintedanib 100 mg twice daily for her IPF and metoprolol 12.5 mg daily for her hypertension. Her pulmonary function test done two years ago showed moderate restrictive lung disease with a forced vital capacity of two liters (77% predicted), total lung capacity of three liters (63% predicted) and diffusion capacity of 58% predicted. Her physical exam was unremarkable. She was placed on isolation precautions because of her clinical presentation and her test for SARS-CoV-2 came back positive (Roche’s Cobas nucleic acid amplification test). She was exposed to her husband who was recently diagnosed with COVID-19. She required three liters of supplemental oxygen for her hypoxemia. Chest radiology showed multifocal consolidations in both lungs (Figure 1).\n\nFigure 1 Chest X-ray\n(A) Chest X-ray done three months prior to presentation shows bilateral interstitial infiltrates predominantly in the lung bases. (B) Chest X-ray done on day 4 of COVID-19 shows worsening bilateral multifocal infiltrates superimposed on chronic changes.\n\nShe received azithromycin and hydroxychloroquine as per the protocol. However, her condition deteriorated requiring 10 liters of supplemental oxygen and on day 3 she was transferred to intensive care unit and intubated for worsening hypoxic respiratory failure. She required 100% fractional concentration of oxygen in inspired gas (FiO2) and 10 cm H2O positive end-expiratory pressure (PEEP) on the ventilator. A limited bedside echocardiogram revealed normal left and right ventricular function. Her inflammatory markers continued to worsen. Ferritin which was 600 ng/mL at the time of her presentation, worsened to 50,480 ng/mL. Her white blood cell (WBC) count was 15,000/mm3 with an absolute lymphocyte count of 800/mm3, procalcitonin was 0.14 ng/mL, D-dimer was 3.3 µg/mL and lactate dehydrogenase (LDH) was 628 IU/L. She received a single intravenous dose of tocilizumab 600 mg. On day 4, she developed severe septic shock and multiorgan dysfunction (worsening renal function, liver function, circulatory collapse and respiratory failure) requiring norepinephrine, vasopressin, phenylephrine and angiotensin II. She was started on intravenous hydrocortisone 100 mg three times daily, but despite all the aggressive measures she died on day 5. We would like to mention that at the time of this patient's presentation, other treatments like convalescent plasma and remdesivir were not readily available. \n\nDiscussion\nChronic lung disease has been reported as a potential risk factor for COVID-19 caused by SARS-CoV-2. In a study that looked at the clinical characteristics and comorbidities in more than 44,000 patients infected with SARS-CoV-2 in China, chronic lung disease had been listed as a comorbidity in only 2.4% of them [1]. On April 8 2020, Centers for Disease Control (CDC) released an early report on the characteristics of hospitalized patients with COVID-19 in the United States, and chronic lung disease was reported as a risk factor in 34.6% of the 159 hospitalized COVID-19 patients [2]. It was also reported that 80% of these patients had obstructive lung disease. On April 29 2020, in the data released by CDC, out of 305 COVID-19 patients in Georgia, chronic respiratory disease was reported as a comorbidity in 20.3% and out of whom 77% had obstructive airway diseases [3]. The prevalence of COVID-19 in IPF has not been reported. IPF is the most common type of idiopathic interstitial pneumonia, characterized by progressive fibrosis with a high fatality rate. The incidence and prevalence of the disease increase with age. IPF is characterized by inflammation and lung injury, and the role of cytokines in its pathogenesis has been well established [4]. There is accumulating evidence that a subgroup of patients with COVID-19 develop cytokine storm syndrome leading to increased mortality from the virus-induced hyperinflammation [5]. It is possible that co-existence of these two fatal disease conditions may significantly affect patient outcomes. On the other hand, survivors of COVID 19 have been reported to develop pulmonary fibrosis as a consequence of dysregulated immune response [6].\n\nConclusions\nPatients living with IPF may not be at increased risk for contracting COVID-19, but probably are at high risk for developing severe fatal complications from the disease. Hence, it is vital to recognize IPF as a potential serious risk factor for COVID-19 complications and IPF patients take the necessary extra precautions advised by CDC to protect themselves and minimize the risk of contracting COVID-19.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet Huang C Wang Y Li X 497 506 395 2020 31986264 \n2 Centers for Disease Control and Prevention: COVID-19 Response Team. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 States, March 1-30 5 2020 2020 https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6915e3-H.pdf \n3 Centers for Disease Control and Prevention: COVID-19 Response Team. Characteristics and clinical outcomes of adult patients hospitalized with COVID-19 - Georgia March 5 2020 2020 https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6918e1-H.pdf \n4 The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis Antioxid Redox Signal Bringardner BD Baran CP Eubank TD Marsh CB 287 302 10 2008 17961066 \n5 COVID- 19: consider cytokine storm syndromes and immunosuppression Lancet Mehta P McAuley DF Brown M 1033 1034 395 2020 32192578 \n6 Advances in the research of mechanism of pulmonary fibrosis induced by Corona Virus Disease 2019 and the corresponding therapeutic measures. [Article in Chinese] Zhonghua Shao Shang Za Zhi Wang J Wang BJ Yang JC 0 36 2020\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(6)", "journal": "Cureus", "keywords": "acute hypoxemic respiratory failure; corona virus; covid-19; idiopathic pulmonary fibrosis; ipf", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e8432", "pmc": null, "pmid": "32642347", "pubdate": "2020-06-03", "publication_types": "D002363:Case Reports", "references": "32298251;17961066;32174095;31986264;32192578", "title": "A Fatal Case of Coronavirus Disease 2019 (COVID-19) in a Patient With Idiopathic Pulmonary Fibrosis.", "title_normalized": "a fatal case of coronavirus disease 2019 covid 19 in a patient with idiopathic pulmonary fibrosis" }	[ { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-031036", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NINTEDANIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IDIOPATHIC PULMONARY FIBROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFEV" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "RAJASURYA V, GUNASEKARAN K, DAMARLA V, KOLLURU A. A FATAL CASE OF CORONAVIRUS DISEASE 2019 (COVID-19) IN A PATIENT WITH IDIOPATHIC PULMONARY FIBROSIS. CUREUS. 12(6):.", "literaturereference_normalized": "a fatal case of coronavirus disease 2019 covid 19 in a patient with idiopathic pulmonary fibrosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200623", "receivedate": "20200623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17930634, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200714" } ]
{ "abstract": "OBJECTIVE\nThe physiological interaction between the intrathecal baclofen (ITB) delivery system and the ventriculoperitoneal (VP) shunting system in a patient who had both systems implanted has not been reported previously. The aim of our report is to evaluate the effect that one system's infection might have on the other.\n\n\nMETHODS\nRecords of children who were followed at our institution between 2004 and 2015 for management of their ITB systems were reviewed. In this group, children who had VP shunts were identified, and those who had any of their ITB or VP systems infected were included.\n\n\nRESULTS\nOut of 313 children managed with ITB therapy at our institution, 31 (24%) children had VP shunts. Two patients had infection in both systems, and 3 patients had infection in 1 system.\n\n\nCONCLUSIONS\nThis report suggests that if aspiration from both systems showed positive cultures, the treatment would be removal of both systems. If the primarily not infected system does not show positive cultures, it does not need to be removed. Close follow-up is recommended, and any sign of infection or malfunction of the primarily not infected device should be approached with a high level of suspicion.", "affiliations": "Department of Orthopaedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.", "authors": "Abousamra\|Oussama\|O\|;Duque Orozco\|Maria Del Pilar\|MDP\|;Rogers\|Kenneth J\|KJ\|;Miller\|Freeman\|F\|;Sees\|Julieanne P\|JP\|", "chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen", "country": "Switzerland", "delete": false, "doi": "10.1159/000475468", "fulltext": null, "fulltext_license": null, "issn_linking": "1016-2291", "issue": "53(1)", "journal": "Pediatric neurosurgery", "keywords": "Infection; Intrathecal baclofen; Spasticity; Ventriculoperitoneal shunt", "medline_ta": "Pediatr Neurosurg", "mesh_terms": "D000293:Adolescent; D001418:Baclofen; D002648:Child; D002675:Child, Preschool; D004866:Equipment Contamination; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central; D017287:Ventriculoperitoneal Shunt; D055815:Young Adult", "nlm_unique_id": "9114967", "other_id": null, "pages": "1-6", "pmc": null, "pmid": "28866663", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": null, "title": "Infections of Intrathecal Baclofen Delivery Systems and Ventriculoperitoneal Shunting Systems: Clinical Series Discussion.", "title_normalized": "infections of intrathecal baclofen delivery systems and ventriculoperitoneal shunting systems clinical series discussion" }	[ { "companynumb": "US-BAUSCH-BL-2017-028163", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPICILLIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENTEROCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENTEROCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GENTAMICIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "64048", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENTEROCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENTAMICIN." } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABOUSAMRA O, OROZCO M, ROGERS K, MILLER F, SEES J. 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{ "abstract": "Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment.", "affiliations": "Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.", "authors": "Iizumi\|Sakura\|S\|;Shimoi\|Tatsunori\|T\|;Nishikawa\|Tadaaki\|T\|;Kitano\|Atsuko\|A\|;Sasada\|Shinsuke\|S\|;Shimomura\|Akihiko\|A\|;Noguchi\|Emi\|E\|;Yunokawa\|Mayu\|M\|;Yonemori\|Kan\|K\|;Shimizu\|Chikako\|C\|;Fujiwara\|Yasuhiro\|Y\|;Tamura\|Kenji\|K\|", "chemical_list": "D050071:Bone Density Conservation Agents; D014807:Vitamin D; D000069448:Denosumab; D002118:Calcium", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8908-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894357410.2169/internalmedicine.8908-17Case ReportProlonged Hypocalcemia Following a Single Dose of Denosumab for Diffuse Bone Metastasis of Gastric Cancer after Total Gastrectomy Iizumi Sakura 1Shimoi Tatsunori 1Nishikawa Tadaaki 1Kitano Atsuko 1Sasada Shinsuke 2Shimomura Akihiko 1Noguchi Emi 1Yunokawa Mayu 1Yonemori Kan 1Shimizu Chikako 1Fujiwara Yasuhiro 1Tamura Kenji 1\n1 Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan\n2 Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, JapanCorrespondence to Dr.　Tatsunori Shimoi, tshimoi@ncc.go.jp\n\n25 9 2017 1 11 2017 56 21 2879 2882 20 1 2017 27 2 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment. \n\ndenosumabhypocalcemiagastrectomygastric cancervitamin Dbone turnover\n==== Body\nIntroduction\nBone metastasis leads to skeletal-related events (SREs), including pathologic fracture, the need for radiation or surgical treatment, and spinal cord compression, all of which impair a patient's quality of life. Clinical studies have shown that bone-modifying agents such as zoledronic acid and denosumab can reduce the incidence of SREs (1-3). Although denosumab has been associated with a lower frequency of SREs than zoledronic acid, it has also been associated with a higher frequency of hypocalcemia (4). We herein report a case of severe persistent hypocalcemia in a patient with diffuse bone metastasis of gastric cancer after the administration of a single dose of denosumab. Furthermore, we have identified potential risk factors for hypocalcemia, particularly gastrectomy, which has not been highlighted previously.\n\nCase Report\nA 77-year-old woman was referred to our hospital to undergo treatment for malignant pleural effusions and dyspnea of 2 months' duration. She had undergone total gastrectomy with D2 lymphadenectomy and Roux-en-Y anastomosis for signet ring cell carcinoma of the stomach (pT1bN2M0, Stage IIA; Japanese Classification of Gastric Carcinoma, 14th Edition) (5) 12 years previously.\n\nShe was hospitalized to be evaluated and treated for dyspnea. Upon admission, her height and weight were 134.1 cm and 43.0 kg (body mass index: 23.9 kg/m2), respectively. Her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 3. A laboratory evaluation yielded the following results: elevated levels of alkaline phosphatase (ALP; 5,680 IU/L, normal range: 115-359 IU/L) and carcinoembryonic antigen (CEA; 5.7 ng/mL, normal range: 0.0-5.0 ng/dL); normal levels of calcium (7.9 mg/dL), corrected calcium [serum calcium + (4 - serum albumin); 8.9 mg/dL, normal range: 8.8-10.1 mg/dL], and creatinine (0.51 mg/mL, normal range: 0.40-0.70 mg/dL). The estimated glomerular filtration rate (eGFR) and estimated creatinine clearance (Cockcroft-Gault equation) were 86 mL/min/1.73 m2 and 62.7 mL/min, respectively. Her initial parathyroid hormone (PTH)-intact level was not measured.\n\nComputed tomography revealed bilateral pleural effusion, ascites, and multiple sclerotic bone lesions without any other visceral metastases. No atrophic change of the kidneys was found. Bone scintigraphy revealed diffuse, increased skeletal activity with little renal activity, which met the definition of a super bone scan (Fig. 1) (6). A cytological evaluation of the pleural effusion detected adenocarcinoma, and a cell block specimen showed adenocarcinoma with signet-ring cells that were positive for Ber-EP4 and HNF4α and negative for ER, PAX8, CDX2, and TTF-1, which was compatible with the patient's history of recurrent gastric cancer. She was diagnosed with pleural dissemination of recurrent gastric cancer and although ascites and bone lesions were not pathologically evaluated due to the challenges associated with specimen collection, these were respectively presumed to be malignant ascites and bone metastases of gastric cancer.\n\nFigure 1. Bone scintigraphy. Diffusely increased activity can be seen in the skeleton. Little activity is observed in the kidneys.\n\nThe patient elected to receive supportive care only, given her general condition and preference. To reduce the risk of SREs and maintain her activities of daily living, she received a single dose of denosumab (120 mg, subcutaneously), and the oral supplementation of calcium (610 mg/day), vitamin D (cholecalciferol) (400 IU/day), and magnesium (30 mg/day) was initiated. She was discharged the day after the administration of denosumab.\n\nSix days after the administration of denosumab, she returned to our hospital via ambulance with paralysis and numbness in the hands. Blood tests revealed hypocalcemia (calcium, 4.7 mg/dL; corrected calcium, 6.0 mg/dL), and hypophosphatemia (phosphate, 2.3 mg/dL, normal range: 2.7-4.6 mg/dL), as well as the following additional values: magnesium, 2.8 mg/mL (normal range: 1.5-2.5 mg/dL); creatinine, 0.49 mg/mL; and ALP, 3605 IU/L. She received an infusion of 10 ml of 10% calcium gluconate (with 3.9 mEq calcium) followed by the continuous intravenous administration of calcium (2.5 mEq/h), after which her calcium level normalized. Twelve days after the administration of denosumab, the oral supplementation of calcium, vitamin D, and magnesium was restarted, and intravenous calcium was reduced to a dose equivalent to 18 mEq/day. Within a few hours, she experienced muscle weakness, and the intravenous calcium dosage was increased. Her PTH-intact level was found to be elevated to 375 pg/mL (normal range: 10-65 pg/mL). Fig. 2 shows the corrected calcium levels and the dose of calcium that was administered intravenously each day. Her general condition deteriorated gradually, with increasing pleural effusion and ascites. She required the intravenous administration of calcium until she was transferred to another hospital for palliative care 56 days later. She died 68 days after the administration of denosumab.\n\nFigure 2. Corrected Ca and intravenous Ca were administered each day. Ca: calcium\n\nDiscussion\nDenosumab, a monoclonal antibody that targets the receptor activator of nuclear factor-κB ligand (RANK-L), prevents bone resorption and bone destruction by inhibiting osteoclast activity (3). Three phase III trials demonstrated the superiority of this agent relative to zoledronic acid for the prevention and delay of SREs in patients with bone metastases of cancer (1-3). As mentioned above, hypocalcemia is a common side effect, which affects 5.5-13% of patients (1-3). Notably, a previous report suggested that RANK-L inhibitors are associated with a greater suppression of bone resorption and calcium release in comparison to bisphosphonates (7).\n\nThe factors associated with an increased risk of hypocalcemia include renal insufficiency, high bone turnover, and lack of vitamin D and calcium supplementation (8, 9). In our case, denosumab-induced hypocalcemia persisted for at least 7 weeks and necessitated the intravenous administration of calcium, despite the oral supplementation of calcium, vitamin D, magnesium, and phosphate. We hypothesize that the patient's history of total gastrectomy, increased bone turnover, and insufficient additional PTH secretion in response to decreased calcium were responsible for the duration and severity of hypocalcemia.\n\nThis report suggests that total gastrectomy with Roux-en-Y anastomosis, rather than gastric cancer, contributed to the development of hypocalcemia. Recently, a retrospective study of patients who received denosumab identified gastric cancer as an independent risk factor for hypocalcemia (10). Because gastrectomy did not increase the risk of hypocalcemia in that analysis, the researchers claimed that a gastrointestinal malfunction in patients with gastric cancer might be a mechanism underlying hypocalcemia, irrespective of gastrectomy. However, fewer than 15 patients with gastric cancer were analyzed in that study, which was the number of cases in which denosumab was administered. Furthermore, the report did not consider the type of gastrectomy (total or partial gastrectomy) or reconstruction.\n\nThe mechanisms of calcium and vitamin D absorption suggest that hypocalcemia associated with total gastrectomy and Roux-en-Y anastomosis is more likely caused by malabsorption. For example, the use of Roux-en-Y anastomosis in bariatric surgery was associated with malabsorption of calcium and vitamin D (11). Another study reported suspected osteomalacia in 25% of post-gastrectomy patients and observed a correlation between fat malabsorption and abnormal calcium metabolism (12). Fat malabsorption is a known complication of gastrectomy with Roux-en-Y anastomosis (13) and can lead to impaired vitamin D absorption, as calcium is ionized and solubilized by gastric acid (14). After total gastrectomy, reduced gastric acid secretion would impair calcium ionization; furthermore, in patients with a Roux-en-Y anastomosis, chyme does not pass through the duodenum, where calcium is primarily absorbed (14). Extra caution should be taken when treating patients who have undergone gastrectomy because they may not absorb orally supplemented calcium or vitamin D. To the best of our knowledge, this is the first case report to demonstrate the possibility of an association between total gastrectomy and denosumab-related hypocalcemia.\n\nDiffuse bone metastases, elevated ALP levels, and a poor PS are reported risk factors for hypocalcemia and may have led to denosumab-induced hypocalcemia in our patient. Although we did not measure the bone-specific ALP level, diffuse bone metastases and an elevated ALP level suggest a high bone metabolism. A pooled analysis of three phase III studies of denosumab found that the number of bone metastases, an elevated bone-specific ALP level, and an elevated urinary N-telopeptide level, which are indicators of high bone turnover, are also risk factors for hypocalcemia (8). Furthermore, a poor PS was reported to be a risk factor for hypocalcemia (10). Altogether, this patient was probably at very high risk of developing denosumab-induced hypocalcemia.\n\nDenosumab-induced hypocalcemia may persist in patients without an appropriate hormonal response to a decreased calcium level. In a phase II study that compared different denosumab doses and dosing schedules, a decrease in a urinary bone turnover marker persisted for 12 weeks after a single dose (15). Thus, bone resorption may be inhibited for at least 12 weeks. The persistence of hypocalcemia may depend on the patient's ability to compensate for this decreased calcium level. Previous case reports have described patients with prolonged denosumab-induced hypocalcemia who required intravenous calcium administration for more than 26 days (16-18). One of these reports identified the potential contributions of a gastrointestinal loss of calcium and normocalcemic hyperparathyroidism (18), with an inability to secrete additional PTH in response to a decreased calcium level. Although the baseline vitamin D, phosphate, and PTH levels were not measured in our case, it was hypothesized that the patient did not respond to decreased calcium levels and experienced persistent hypocalcemia requiring intravenous calcium administration for more than 50 days due to a gastrectomy-related loss of calcium and preexisting normocalcemic hyperparathyroidism.\n\nThe present study is associated with some limitations. First, it is possible that the PTH-intact level increased due to chronic renal dysfunction as the baseline PTH-intact level was not measured and the assessment of the patient's kidney function was not thorough (24-hour urine collection was not performed). However, with the available data on the patient's renal function and the rarity (8%) of PTH-intact elevation (≥70 pg/mL) in patients with an eGFR of ≥60 mL/min/1.73 m2 (19), we believe that a marked increase in the PTH-intact level due to chronic renal dysfunction was unlikely. Second, in the present study, we only report one case. The association between gastrectomy and denosumab-induced hypocalcemia needs to be further evaluated in a larger number of patients with and without prior total gastrectomy. Nonetheless, it would be meaningful for clinicians to keep in mind the possibility that gastrectomy may increase the risk of denosumab-induced hypocalcemia and to identify potentially high-risk patients.\n\nTotal gastrectomy with Roux-en-Y anastomosis may be a risk factor for denosumab-induced hypocalcemia. This condition can persist in patients with impaired hormonal responses to decreased calcium levels. It is important to thoroughly evaluate bone and calcium homeostasis, including the nutritional status associated with gastrointestinal manipulation, and the extent of bone metastasis and turnover prior to the initiation of denosumab therapy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nStopeck AT , Lipton A , Body JJ , et al \nDenosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study . J Clin Oncol \n28 : 5132 -5139 , 2010 .21060033 \n2. \nFizazi K , Carducci M , Smith M , et al \nDenosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study . Lancet \n377 : 813 -822 , 2011 .21353695 \n3. \nHenry DH , Costa L , Goldwasser F , et al \nRandomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma . J Clin Oncol \n29 : 1125 -1132 , 2011 .21343556 \n4. \nLipton A , Fizazi K , Stopeck AT , et al \nSuperiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials . Eur J Cancer \n48 : 3082 -3092 , 2012 .22975218 \n5. \nJapanese classification of gastric carcinoma: 3rd English edition . Gastric Cancer \n14 : 101 -112 , 2011 .21573743 \n6. \nManier SM , Van Nostrand D \nSuper bone scan . Semin Nucl Med \n14 : 46 -47 , 1984 .6710165 \n7. \nMorony S , Warmington K , Adamu S , et al \nThe inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy . Endocrinology \n146 : 3235 -3243 , 2005 .15845617 \n8. \nBody JJ , Bone HG , de Boer RH , et al \nHypocalcaemia in patients with metastatic bone disease treated with denosumab . Eur J Cancer \n51 : 1812 -1821 , 2015 .26093811 \n9. \nWatkins KR , Rogers JE , Atkinson B \nTolerability of denosumab in metastatic solid tumor patients with renal insufficiency . Support Care Cancer \n23 : 1657 -1662 , 2015 .25421444 \n10. \nKinoshita Y , Arai M , Ito N , et al \nHigh serum ALP level is associated with increased risk of denosumab-related hypocalcemia in patients with bone metastases from solid tumors . Endocr J \n31 : 479 -484 , 2016 .\n11. \nBland CM , Quidley AM , Love BL , Yeager C , McMichael B , Bookstaver PB \nLong-term pharmacotherapy considerations in the bariatric surgery patient . Am J Health Syst Pharm \n73 : 1230 -1242 , 2016 .27354038 \n12. \nEddy RL \nMetabolic bone disease after gastrectomy . Am J Med \n50 : 442 -449 , 1971 .5572594 \n13. \nStael von , Holstein C , Walther B , Ibrahimbegovic E , Akesson B \nNutritional status after total and partial gastrectomy with Roux-en-Y reconstruction . Bri J Surg \n78 : 1084 -1087 , 1991 .\n14. \nBronner F , Pansu D \nNutritional aspects of calcium absorption . J Nutr \n129 : 9 -12 , 1999 .9915868 \n15. \nLipton A , Steger GG , Figueroa J , et al \nRandomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases . J Clin Oncol \n25 : 4431 -4437 , 2007 .17785705 \n16. \nShafqat H , Alquadan KF , Olszewski AJ \nSevere hypocalcemia after denosumab in a patient with acquired Fanconi syndrome . Osteoporos Int \n25 : 1187 -1190 , 2014 .24158473 \n17. \nTeng J , Abell S , Hicks RJ , et al \nProtracted hypocalcaemia following a single dose of denosumab in humoral hypercalcaemia of malignancy due to PTHrP-secreting neuroendocrine tumour . Clin Endocrinol \n81 : 940 -942 , 2014 .\n18. \nMilat F , Goh S , Gani LU , et al \nProlonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer . Bone \n55 : 305 -308 , 2013 .23685544 \n19. \nMuntner P , Jones TM , Hyre AD , et al \nAssociation of serum intact parathyroid hormone with lower estimated glomerular filtration rate . Clin J Am Soc Nephrol \n4 : 186 -194 , 2009 .19019998\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(21)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "bone turnover; denosumab; gastrectomy; gastric cancer; hypocalcemia; vitamin D", "medline_ta": "Intern Med", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D002118:Calcium; D000069448:Denosumab; D005260:Female; D005743:Gastrectomy; D006801:Humans; D006996:Hypocalcemia; D012307:Risk Factors; D013274:Stomach Neoplasms; D014807:Vitamin D", "nlm_unique_id": "9204241", "other_id": null, "pages": "2879-2882", "pmc": null, "pmid": "28943574", "pubdate": "2017-11-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25421444;26860123;22975218;21343556;24158473;21573743;9915868;19019998;26093811;1933192;15845617;17785705;21060033;6710165;27354038;21353695;5572594;24890549;23685544", "title": "Prolonged 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{ "abstract": "A 77-year-old African American female with rheumatoid arthritis presented with fever and unsteady gait. She was started on broad-spectrum antimicrobials due to CT evidence for sacroiliitis and psoas abscess and underwent partial excision of her sacroiliac bone and drainage of the abscess. One of four blood cultures grew Enterococcus faecalis and the patient was sent home with intravenous ampicillin for 6 weeks. Two days after antimicrobial completion, the patient presented with night sweats and weakness. Chest x-ray revealed new right upper lobe pulmonary infiltrates, and the AFB culture sent during her prior admission returned positive for TB. RIPE therapy with moxifloxacin was initiated. Although she responded well to treatment, she retained functional immobility. We report a case of musculoskeletal TB initially misdiagnosed as enterococcus sacroiliitis, resulting in a delayed initiation of anti-tuberculous therapy. A high index of suspicion and rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis.", "affiliations": "Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.", "authors": "Chandradevan\|Raguraj\|R\|;Takeda\|Hironobu\|H\|;Lim\|Tanna\|T\|;Patel\|Nidhip\|N\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2020.e00858", "fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30166-9\n10.1016/j.idcr.2020.e00858\ne00858\nArticle\nMycobacterium tuberculosis concealed by enterococcal sacroiliitis\nChandradevan Raguraj Takeda Hironobu Lim Tanna Patel Nidhip nidhip.patel@northside.com⁎ Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA\n⁎ Corresponding author at: Internal Medicine/Graduate Medical Education, Northside Hospital Gwinnett, 1000 Medical Center Blvd, Lawrenceville, GA, 30046, USA. nidhip.patel@northside.com\n01 6 2020 \n2020 \n01 6 2020 \n21 e0085818 5 2020 29 5 2020 29 5 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 77-year-old African American female with rheumatoid arthritis presented with fever and unsteady gait. She was started on broad-spectrum antimicrobials due to CT evidence for sacroiliitis and psoas abscess and underwent partial excision of her sacroiliac bone and drainage of the abscess. One of four blood cultures grew Enterococcus faecalis and the patient was sent home with intravenous ampicillin for 6 weeks. Two days after antimicrobial completion, the patient presented with night sweats and weakness. Chest x-ray revealed new right upper lobe pulmonary infiltrates, and the AFB culture sent during her prior admission returned positive for TB. RIPE therapy with moxifloxacin was initiated. Although she responded well to treatment, she retained functional immobility. We report a case of musculoskeletal TB initially misdiagnosed as enterococcus sacroiliitis, resulting in a delayed initiation of anti-tuberculous therapy. A high index of suspicion and rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis.\n\nKeywords\nMusculoskeletal tuberculosisDiagnostic delaysIliopsoas abscess\n==== Body\nIntroduction\nTuberculosis is a leading cause of death worldwide [1]. Even though considerable progress has been made in reducing incidence in United States, the goal of eliminating the disease from the US remains elusive [2]. Lengthy treatment duration and delay in diagnosis are associated with multidrug-resistant and extensively drug-resistant tuberculosis. Proactive screening for tuberculosis using best available diagnostics, making accurate and early diagnoses of drug-sensitive or drug-resistant tuberculosis, and initiating appropriate treatment are crucial steps to reduce morbidity and further transmission within the community [3]. Approximately 20–30% of reported cases purely involve extrapulmonary sites. Skeletal tuberculosis is reported in 3–5% of cases [4]. The lack of suspicion, long culture period, and scant experience of providers accounts for a delay between the initial symptoms and the definite diagnosis of skeletal tuberculosis [5]. Our case represents the presence of another organism with tuberculosis, creating a diagnostic dilemma of musculoskeletal tuberculosis and explains the usefulness of rapid detection with TB-PCR to avoid the delay in diagnosis.\n\nCase report\nA 77-year-old African American female with hypertension and rheumatoid arthritis on chronic prednisone therapy presented to the hospital with fever, weakness, and unsteady gait. The patient had a history of latent tuberculosis infection reportedly treated over 15 years ago, and abdominal lymphadenopathy with granulomatous histology of unknown etiology three years ago. Laboratory testing showed normal hemoglobin, elevated leukocyte count of 35,000 cells/μL, and normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Her liver and kidney function were normal, and electrolytes were within normal limits. Physical examination revealed high fever and limited left hip mobility due to weakness and pain. Computed tomography of the hip joint revealed progressive destruction of her sacroiliac joint and a 10 × 8 × 7-centimeter (cm) fluid collection in front of her left iliopsoas muscle (Fig. 1, Fig. 2). A presumptive diagnosis of pyogenic sacroiliitis and psoas abscess were made and the patient was placed on broad-spectrum antimicrobials.Fig. 1 Left psoas abscess (red arrows) and destructive sacroiliac joint (green arrow) in an axial computed tomography scan with intravenous contrast (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).\n\nFig. 1Fig. 2 Coronal section in an abdomen and pelvis computed tomography scan with intravenous contrast showing the left psoas abscess.\n\nFig. 2\n\nThe patient underwent saucerization and partial excision of her left ilium and sacrum, surgical placement of antimicrobial beads, and drainage of the psoas abscess. Biopsy from the bone and drainage from the psoas abscess were also sent for further evaluation. The bone biopsy revealed ill-defined granulomas and the gram stain, AFB stain, GMS stain. and bacterial cultures of the psoas drainage were negative. Samples were sent for tuberculosis and fungal cultures. One out of four blood culture bottles grew Enterococcus faecalis sensitive to ampicillin. Given that all other testing was negative, the patient was sent to a nursing home with intravenous ampicillin therapy for a six-week course. Two days after completing treatment, the patient presented to the hospital again with recurrence of symptoms especially with nightly high fevers and weakness. Laboratory findings were only significant for an elevated WBC of 12,000 cells/μL. CT revealed healing sacroiliitis, no obvious new abscess, and post-surgical placement of antimicrobial beads (Fig. 3). Initial consideration was incomplete treatment given the timing of the symptoms after cessation of antimicrobials; however, the previous AFB culture coincidentally was found to be positive in the seventh week, and TB was confirmed by PCR from the culture positive samples. During the initial encounter,the patient underwent a CXR as a routine work up which didn’t show any infiltrates; however during further work up after the AFB culture, a CXR was repeated and revealed new right upper lobe infiltrates suggestive of pulmonary tuberculosis (Fig. 4).Fig. 3 Axial computed tomography film with intravenous contrast during the second presentation showing post surgical drainage and antimicrobial beads placed (blue) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).\n\nFig. 3Fig. 4 Postero-anterior chest X ray film showing right upper lobe infiltrates.\n\nFig. 4\n\nThe patient did not present with respiratory symptoms; however, she was placed in respiratory isolation and sputum was tested for AFB. She was started on rifampin, isoniazid, pyrazinamide and ethambutol (RIPE) therapy, with the addition of moxifloxacin to also cover for multi-drug resistant tuberculosis (MDR-TB). The patient’s fever subsided after one week of treatment, and after two weeks of treatment she markedly improved and had negative AFB smear and PCR on induced sputum. She was released from isolation precautions and discharged with follow up with the public health department. At the time of discharge, the patient exhibited functional decline and deconditioning due to prolonged hospital stay as well as chronic debilitating illness. She was assessed by physical therapy using Barthel Index score which is a measurement of activities of daily living and revealed a value of 45 points and partially independent. She was placed in a sub-acute rehabilitation facility after inpatient hospital discharge.\n\nDiscussion\nIn skeletal tuberculosis, the onset of symptoms is generally insidious, and not accompanied by alarming general manifestations such as fever, night sweats or extreme weakness [6]. In tuberculous sacroiliitis, there is usually considerable delay between presentation and diagnosis, mainly due to its insidious onset, nonspecific clinical picture, and low clinical index of suspicion. Studies have reported a mean time from symptom onset to diagnosis of 8 months in a series of sacroiliac joint tuberculosis [7]. The diagnosis in our patient was also delayed for 6 weeks despite the recognition and drainage of psoas abscess and pathological analysis of debrided tissue. This is probably due to an atypical clinical picture of tuberculosis and presence of concomitant bacteremia.\n\nA definitive diagnosis of skeletal tuberculosis can be made based on findings of the culture and pathological tests of infected tissues, but these cultures are only positive at a rate of 50–75 %, making bacteriologic confirmation of the disease very difficult [8]. RT-PCR assays have a high degree of sensitivity, making them a suitable test to rule out TB infection. RT-PCR assays demonstrate rapidity of detection of TB, which is an important factor in initiating early and appropriate anti-tuberculosis therapy. PCR can play an important role in rapid and accurate diagnosis of extrapulmonary tuberculosis. The percentage of specimen positive by smear, culture, and PCR was 20.3%, 23.6 %, and 45.3%, respectively, for the diagnosis of extrapulmonary tuberculosis in one study [9].\n\nThe rapid results of PCR aid in early institution of anti-tuberculosis treatment and thus controlling the spread of disease. Further, in this case, it was difficult to detect the tubercle bacilli until the culture became positive. Moreover, we were hesitant to start anti-tuberculosis medications in the setting of enterococcal bacteremia. During the six weeks course of treatment patient did not have a fever and pain was markedly reduced to ease her participation in physical therapy. We believe this is due to radical debridement of the sacroiliitis and treatment response to co-existing bacterial sacroiliitis. Presence of tuberculosis with bacterial infections in immunocompetent patients has been reported in the past, and we believe our patient acquired concomitant infectious processes with enterococcal bacteremia and mycobacteria infection [10]. Negative bacterial culture and stains from the abscess, enterococcal bacteremia and treatment response with ampicillin appropriately dictated immediate antimicrobial therapy; however, it caused anchoring to a diagnosis without considering the patient’s high risk for concomitant TB.\n\nIn the case of an elderly woman with known TB exposure, chronic immunosuppression secondary to prednisone therapy, pyogenic abscess to an area typical for TB, granulomatous pathology of bone biopsy, and previous biopsy with granulomatous nodules in the abdomen should have led to earlier PCR testing or empiric TB treatment on initial presentation. TB is a slow growing acid-fast bacillus and waiting for culture results can cause a delay in diagnosis and further morbidity, as in our case.\n\nConclusion\nTuberculous sacroiliitis is a disabling condition and can often be overlooked. Keeping a high index of suspicion for TB in high-risk individuals and considering more rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis and increased morbidity from delay in treatment.\n\nAuthor contributions\nRaguraj Chandradevan helped conceptualize the paper, contributed to data acquisition, wrote the manuscript, and reviewed and approved the final manuscript.\n\nHironobu Takeda and Tanna Lim helped conceptualize the paper, contributed to data acquisition, and reviewed and approved the final manuscript.\n\nNidhip Patel is the investigator of this project and responsible for the overall conduct, results and conclusions of the paper. He conceptualized the paper, contributed to the manuscript, and reviewed and approved the final manuscript.\n\nFunding\nThere was no funding or sponsorship for this report.\n\nEthical approval\nThis study was approved by Graduate Medical Education at Northside Hospital Gwinnett.\n\nConsent\nWe obtained the patient’s consent to publish the case report. The patient accepts the publication of this case report.\n\nDeclaration of Competing Interest\nThe authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Glaziou P. Sismanidis C. Floyd K. Raviglione M. Global epidemiology of tuberculosis Cold Spring Harb Perspect Med 5 2 2014 a017798 \n2 Langer A.J. Navin T.R. Winston C.A. LoBue P. Epidemiology of tuberculosis in the United States Clin Chest Med 40 4 2019 693 702 31731978 \n3 Gilpin C. Korobitsyn A. Weyer K. Current tools available for the diagnosis of drug-resistant tuberculosis Ther Adv Infect Dis 3 6 2016 145 151 28386407 \n4 Pigrau-Serrallach C. Rodriguez-Pardo D. Bone and joint tuberculosis Eur Spine J 22 Suppl 4 2013 556 566 \n5 Broderick C. Hopkins S. Mack D.J.F. Aston W. Pollock R. Skinner J.A. Delays in the diagnosis and treatment of bone and joint tuberculosis in the United Kingdom Bone Joint J 100–B 1 2018 119 124 \n6 Garg R.K. Somvanshi D.S. Spinal tuberculosis: a review J Spinal Cord Med 34 5 2011 440 454 22118251 \n7 Zhu G. Jiang L.Y. Yi Z. Ping L. Duan C.Y. Yong C. Sacroiliac joint tuberculosis: surgical management by posterior open-window focal debridement and joint fusion BMC Musculoskelet Disord 18 1 2017 504 29187182 \n8 Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence Clin Microbiol Rev 16 3 2003 463 496 12857778 \n9 Raveendran R. Wattal C. Utility of multiplex real-time PCR in the diagnosis of extrapulmonary tuberculosis Braz J Infect Dis 20 3 2016 235 241 27020707 \n10 Attia E.F. Pho Y. Nhem S. Sok C. By B. Phann D. Tuberculosis and other bacterial co-infection in Cambodia: a single center retrospective cross-sectional study BMC Pulm Med 19 1 2019 60 30866909\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "21()", "journal": "IDCases", "keywords": "Diagnostic delays; Iliopsoas abscess; Musculoskeletal tuberculosis", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "e00858", "pmc": null, "pmid": "32566481", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "31731978;29187182;25359550;22711012;30866909;27020707;29305460;12857778;28386407;22118251", "title": "Mycobacterium tuberculosis concealed by enterococcal sacroiliitis.", "title_normalized": "mycobacterium tuberculosis concealed by enterococcal sacroiliitis" }	[ { "companynumb": "US-TEVA-2020-US-1802811", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated tuberculosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Loss of personal independence in daily activities", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sacroiliitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CHANDRADEVAN R, TAKEDA H, LIM T, PATEL N. MYCOBACTERIUM TUBERCULOSIS CONCEALED BY ENTEROCOCCAL SACROILIITIS. IDCASES 2020?:.", "literaturereference_normalized": "mycobacterium tuberculosis concealed by enterococcal sacroiliitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20200721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18050793, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]
{ "abstract": "To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586.\n\n\n\nA randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models.\n\n\n\nThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low.\n\n\n\nNo clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges.\n\n\n\nNCT01526057.", "affiliations": "Pfizer Inc., San Diego, California, USA.;Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., New York, New York, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., Cambridge, Massachusetts, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., Cambridge, Massachusetts, USA.;Pfizer Inc., San Diego, California, USA.", "authors": "Williams\|Jason H\|JH\|;Hutmacher\|Matthew M\|MM\|;Zierhut\|Matthew L\|ML\|;Becker\|Jean-Claude\|JC\|;Gumbiner\|Barry\|B\|;Spencer-Green\|George\|G\|;Melia\|Lisa A\|LA\|;Liao\|Kai-Hsin\|KH\|;Suster\|Matthew\|M\|;Yin\|Donghua\|D\|;Li\|Ruifeng\|R\|;Meng\|Xu\|X\|", "chemical_list": "D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; D000069283:Rituximab", "country": "England", "delete": false, "doi": "10.1111/bcp.13094", "fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin Pharmacol10.1111/(ISSN)1365-2125BCPBritish Journal of Clinical Pharmacology0306-52511365-2125John Wiley and Sons Inc. Hoboken 2753037910.1111/bcp.13094BCP13094MP-00054-16.R1Pharmacokinetic Dynamic RelationshipsPharmacokinetic Dynamic RelationshipsComparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab Comparative assessment of clinical response for PF‐05280586 and rituximabJ. H. Williams et al.Williams Jason H. \n1\nHutmacher Matthew M. \n2\nZierhut Matthew L. \n1\nBecker Jean‐Claude \n3\nGumbiner Barry \n1\nSpencer‐Green George \n4\nMelia Lisa A. \n1\nLiao Kai‐Hsin \n1\nSuster Matthew \n1\nYin Donghua donghua.yin@pfizer.com \n1\nLi Ruifeng \n4\nMeng Xu \n1\n1 Pfizer Inc.San DiegoCaliforniaUSA2 Ann Arbor Pharmacometrics GroupAnn ArborMichiganUSA3 Pfizer Inc.New YorkNew YorkUSA4 Pfizer Inc.CambridgeMassachusettsUSA* Correspondence Donghua Yin, Pfizer Inc, 10777 Science Center Drive, CB1, San Diego, California 92121, USA. Tel.: +1 858 526 4942; E‐mail: donghua.yin@pfizer.com22 9 2016 12 2016 22 9 2016 82 6 10.1111/bcp.v82.61568 1579 19 1 2016 08 7 2016 08 8 2016 © 2016 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Aims\nTo evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586.\n\nMethods\nA randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models.\n\nResults\nThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low.\n\nConclusions\nNo clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: NCT01526057.\n\nBiosimilarpharmacodynamicspharmacokinetics source-schema-version-number2.0component-idbcp13094cover-dateDecember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:24.11.2016\n\n\nWilliams , J. H. \n, \nHutmacher , M. M. \n, \nZierhut , M. L. \n, \nBecker , J. ‐C. \n, \nGumbiner , B. \n, \nSpencer‐Green , G. \n, \nMelia , L. A. \n, \nLiao , K. ‐H. \n, \nSuster , M. \n, \nYin , D. \n, \nLi , R. \n, and \nMeng , X. \n (2016 ) Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab . Br J Clin Pharmacol , 82 : 1568 –1579 . doi: 10.1111/bcp.13094.27530379\n==== Body\nWhat is Already Known about this Subject\n\nPharmacodynamics and clinical response data collected during early clinical pharmacology studies can add to the totality of the evidence, reduce residual uncertainty, in support of the overall demonstration of biosimilarity, as described in regulatory guidance. However, no report is available to share the knowledge on and experience with this topic.\n\n\n\n\nWhat this Study Adds\n\nThis analysis introduces an objective approach to define ‘meaningful effect’ and quantifies a reference range in which to perform comparative assessments.\n\nModel‐based approaches may help reduce the number of studies necessary to demonstrate biosimilarity to bring affordable versions of biologics to patients who otherwise have no or limited access.\n\n\n\n\nTables of Links\n\n\nTARGETS\n\t\t\n\nOther protein targets\n2\n\t\t\n\nCD20\n\t\nTNF‐alpha\n\t\n\nLIGANDS\n\t\t\n\nRituximab\n\t\t\nThese Tables lists key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.\n\n\n\n\nIntroduction\nTherapies based on biologics are increasingly important in treating many diseases due to their success in addressing previously unmet medical needs. In particular, biologics have greatly improved the management of rheumatoid arthritis (RA), demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion and preventing loss of function 3. However, access to biologic medicines can be limited, particularly in resource‐constrained countries 4. Biosimilars, biologic products that are highly similar to a reference product in terms of quality, biological activity, safety and efficacy, are expected to be an essential component in reducing health care costs and enhancing patient access to these important, often lifesaving medications 4. In the USA, the Biologics Price Competition and Innovation Act of 2009 established an abbreviated pathway for US Food and Drug Administration (FDA) licensure of products that are biosimilar to a licensed reference product 5. Similar regulatory pathways for biosimilar applications have been established elsewhere 6, 7. A key component of the abbreviated pathway is extrapolation of clinical data to one or more additional indications 6, 8.\n\nThe role of clinical pharmacology studies in demonstration of biosimilarity is emphasised in the FDA's guidance for industry 9. These studies provide data that describe the degree of similarity in drug exposure, also referred to as pharmacokinetic (PK) similarity, between the proposed biosimilar and reference product(s). In addition, clinical pharmacology studies often include pharmacodynamic (PD) end points and pharmacometric analyses to assess whether clinically meaningful differences exist between the proposed biosimilar and reference product(s). Clinical pharmacology data can add to the totality of the evidence and reduce residual uncertainty, thus guiding the need for, and design of, subsequent clinical testing. Furthermore, clinical pharmacology data can provide scientific justification supporting extrapolation of clinical data to one or more additional indications.\n\nRituximab is a chimeric anti‐CD20 monoclonal antibody that selectively targets and depletes B cells and has demonstrated significant clinical benefit in patients with RA and non‐Hodgkin's lymphoma 10, 11. PF‐05280586 has the same primary amino acid sequence as rituximab, with similar physicochemical and in vitro functional properties, and is under development as a potential biosimilar to rituximab 12, 13. The PK similarity of PF‐05280586 to rituximab sourced from the European Union (rituximab‐EU) and US (rituximab‐US), as well as PK similarity of rituximab‐EU to rituximab‐US, was demonstrated in a multicentre, multinational, randomised double‐blind, controlled trial in patients with active RA on a background of methotrexate who had an inadequate response to one or more tumour necrosis factor antagonist therapies 12. Use of reference products sourced from different regions (i.e. EU and US) is part of standard PK similarity study design for not only meeting the reference‐specific PK similarity requirement but also for providing scientific justification for use of a single reference product in subsequent trials 8.\n\nThis trial was designed to demonstrate PK similarity, yet clinical response end points were also collected during the 24‐week study period. The study was therefore not powered for standard statistical evaluation of efficacy. Using a population PK/PD (PopPK/PD) modelling approach that was planned prospectively, analysis of clinical end points was conducted to assess any potential clinically meaningful difference between the proposed biosimilar and a reference product. The approach took advantage of the multiple repeated measurements for each clinical end point and variability observed between the two reference products using the assumption that differences in clinical responses between the two reference products would not be clinically meaningful if PK similarity was established. The key aspect of this approach was to utilise data from the two reference arms for constructing a reference range of ‘no clinically meaningful difference’ for comparative assessments of PF‐05280586 to the reference products. We present this PopPK/PD modelling analysis as a case study for utilizing clinical response data from a clinical pharmacology study to add to the overall demonstration of biosimilarity.\n\nMethods\nThis study is registered at ClinicalTrials.gov (NCT01526057) and was conducted in compliance with the Declaration of Helsinki and with all International Conference on Harmonisation Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol, amendments and informed consent documentation were reviewed and approved by Institutional Review Boards and/or Independent Ethics Committees at each participating centre. A signed and dated informed consent was required from each patient before any screening procedures were conducted.\n\nStudy design\nThe study was a randomised, double‐blind, controlled trial in patients with active RA on a background of methotrexate who had inadequate responses to one or more tumour necrosis factor antagonist therapies 12. The primary objective was to demonstrate PK similarity of PF‐05280586, rituximab‐EU and rituximab‐US. The secondary objectives included those described herein, which were to use PopPK/PD modelling approaches to integrate PK and PD data for the purpose of detecting potential differences in PK/PD profiles. Other secondary objectives included evaluation of overall safety, tolerability and immunogenicity. The results of this study, except for those from the PopPK/PD modelling, have been presented elsewhere 12. Full details of the study design have been described 12. Briefly, eligible participants were adults (aged ≥18 years) with confirmed diagnosis of RA based on 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria 14. Patients were required to: meet class I, II or III of the ACR 1991 revised criteria for Global Functional Status in Rheumatoid Arthritis 15; have RA seropositivity, as documented by a screening assessment for rheumatoid factor; and/or anticyclic citrullinated peptide antibodies; active disease, as defined by the following: at least six tender/painful joints (of 68 assessed) and six or more swollen joints (of 66 assessed) at screening and baseline, high‐sensitivity C‐reactive protein (CRP) greater than the upper limit of normal, or Patient's Global Assessment of arthritis score ≥50 at screening, and Disease Activity Score in 28 joints (DAS28)–CRP >3.2 at screening; be on a stable dose of oral or parenteral methotrexate 10–25 mg per week (or as low as 7.5 mg per week, in the case of prior poor tolerance) for at least 3 months and receiving the stable dose for at least 4 weeks prior to first dose of study drug; and have inadequate response, in the opinion of the investigator, to one or more approved TNF‐antagonist therapies, defined as failure to achieve adequate clinical response during prior TNF‐antagonist therapy, relapse following clinical response to TNF‐antagonist therapy or an adverse event resulting in discontinuation of TNF antagonist. A sample size calculation based on standard bioequivalence determined that up to 210 subjects were to be enrolled to ensure at least 195 subjects (65 subjects in each treatment arm) completed the study procedures per protocol. The PopPK/PD analysis population was defined as all randomised subjects who receive full doses of the assigned study treatment and had at least one protocol‐specified measurement for drug concentration and the PD response of interest collected after receiving study treatment, as well as the respective baseline values. Patients received 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US by intravenous infusion on days 1 and 15. All subjects were to receive premedication with 100 mg intravenous methylprednisolone (or its equivalent) prior to each infusion.\n\nClinical response\nEfficacy following rituximab therapy in patients with RA included improvements in measures of clinical response such as DAS28 and categorical American College of Rheumatology (ACR) response 16, 17, 18. DAS28 is a function of four components: tender joint counts 28 (TJ28) and swollen joint counts 28 (SJ28), CRP and patient's global assessment of arthritis (PGA). The ACR responder criteria are a function of a core set of seven components: TJ68, SJ66, CRP, PGA, Health Assessment Questionnaire Disability Index, patient's assessment of arthritis pain, and physician's global assessment of arthritis. A patient was considered a responder on the ACR20 assessment if >20% improvement in tender and swollen joint counts was observed with >20% improvement in three of the five other component variables; ACR50 and ACR70 were defined similarly, with 50% and 70% thresholds, respectively. Components of DAS28 and ACR responder status end points were collected at predose (baseline) and at 2, 4, 8, 12, 16, 20 and 24 weeks after start of treatment.\n\nAn enzyme‐linked immunosorbent assay for determining concentrations of rituximab and PF‐05280586 in human serum samples was developed and validated by QPS, LLC (Newark, DE, USA; see Supplemental Methods). Actual time of collection for all PK and clinical response measurements was used for the analysis.\n\nModel development and implementation\nLongitudinal nonlinear mixed‐effects models were fit to the PK, DAS28 and ACR response data. The models were implemented in NONMEM (Icon Development Solutions, Ellicott City, MD, USA), version 7.1.2 or higher, using first‐order conditional estimation for continuous end points and Laplace estimation for categorical end points. The models were similar to those described for characterization of the time‐course of both continuous 19 and categorical 20, 21, 22, 23 measures of clinical response in patients with RA. As previously described, these models provide a semi‐mechanistic framework to describe the effect functions for both placebo and drug, each of which can include parameters related to the effect onset and maximum. This is more intuitive for continuous end points. For categorical end points, an underlying unobservable ‘latent variable’ (LV) is mapped into binary or ordered categorical response through the probability mass between thresholds. In this way, the threshold parameter is a numerical value on the unobservable continuous scale, which determines positivity on the binary scale. The LV is often assumed to be a function of an indirect response mechanism (e.g. reduction of inflammation) and any acting placebo effects (e.g. a patient's perception of their disease) which may be aggregated into a single clinical response end point (e.g. ACR response rate). Constructing the LV as a function of the indirect response thus yields a pharmacologically interpretable type of model and therefore may be useful for assessing similarity of response between two drug products. In addition, for a more efficient use of ACR response data, simultaneous modelling of ACR20, ACR50 and ACR70 end points were implemented, assuming that ACRm, where m = 20, 50 or 70, was achieved when an m% improvement form baseline was observed 19.\n\nCovariate effects were modelled focusing on components of baseline disease activity appropriate for each clinical response end point, which are centred on their median observed values, and product specific parameters applied to three key model components and were estimated simultaneously. Detailed mathematical descriptions of structures for DAS28 change from baseline (DAS28cfb) and ACR responder models, and procedures for their suitability evaluations and applications for comparative assessments are provided in Supplemental Methods.\n\nReference range for comparative assessments\nThe rationale for using the reference range to define ‘clinically meaningful effect’ relied on the assumption that differences in clinical responses between the two reference products would not be clinically meaningful if PK similarity was established. This assumption is based on the following: two rituximab reference products, while sourced from different regions, share the same prescribing practice for the indications approved in the regions, consistent with the biosimilarity definition based on the principle of no clinically meaningful differences between two biologic products under consideration; and confirmation that equivalent exposures were achieved in the two reference products ensuring that any difference in clinical response between the two are not due to differing exposure.\n\nThe 90% confidence interval (CI) of the model‐predicted difference between area under effect curve (AUEC) means of rituximab‐EU and rituximab‐US treatments defined the reference range for a given clinical response end point. The model predictions of AUEC differences between means for PF‐05280586 and rituximab‐US and between PF‐05280586 and rituximab‐EU were compared with the reference range. Predictions within the reference range implied that no meaningful difference was observed between PF‐05280586 and the reference.\n\nComparative assessments\nMonte Carlo techniques (1000 simulation replicates of 10 000 individuals per arm) were used to derive the 90% CIs used for the comparative assessments. A smoothed parametric bootstrap procedure was used to generate the Monte Carlo replicates in which vectors of parameters were drawn for each simulated replicate from a multivariate normal distribution, with mean vector equal to the population model estimates and uncertainty incorporated via the estimated covariance matrix of these population estimates. Additionally, a covariate vector for each individual within the replicate was sampled from the empirical distribution of the study using a bootstrap technique with replacement of patients during resampling. The bootstrap technique was not stratified by treatment to ensure covariate distributions were balanced on average across the groups over the simulated replicates. From these simulated data, population AUEC means were computed across the individual and the covariate distribution per replicate and per arm to derive the prediction for the replicate. The predictions were not dependent upon the individual covariate effects, because these were integrated from the population mean prediction. Thus, differences between treatments were based on fixed effects of treatment differences and their uncertainties. The 90% CI was calculated using the 5th and 95th percentile from the distribution of the AUEC differences between the test and reference products.\n\nCase–control analysis\nA posthoc case–control analysis was performed as an orthogonal approach to verifying the impact of the imbalance in baseline patient disease characteristics among groups on the comparative assessments. Multivariate and propensity score matching was implemented using the Matching package in R Software (R Foundation for Statistical Computing, Vienna, Austria) 24. Variables selected for inclusion in the propensity score model were based on those that showed an imbalance in the original dataset while also considering observed correlations between different variables. Matching was performed without replacement of subjects using a calliper of one‐quarter the standard deviation of the propensity score. For a given propensity score model, matching was performed first to balance the two reference groups (rituximab‐EU vs. rituximab‐US) using 1:1 matching. The two matched reference groups were then compared for how well balance was achieved. If adequate, matching was then performed using the same propensity score model to balance the reference group (rituximab‐EU/US) to the test group (PF‐05280586) using 2:1 matching. The matched groups were then compared for how well balance was achieved. This process was repeated for various models, which included either a single or multiple variables. Performance was assessed at each step graphically and statistically. Graphical comparison of clinical response measures (DAS28cfb and ACR20 responder rate) between the three balanced treatment groups was performed to show the effects of matching.\n\nResults\nBaseline characteristics\nA total of 214 patients were included in the PopPK/PD modelling analysis population (Table 1). Demographics were similar across groups; however, some imbalances with respect to baseline disease characteristics and duration of RA were noted. Specifically, patients in the rituximab‐US arm had the highest baseline DAS28 with a CRP component, as well as the highest mean values of the individual components that make up DAS28 and ACR assessments. The most noticeable differences were in CRP; PGA and physician's global assessment of arthritis based on visual analogue scale measurements; SJ28 and SJ66; and TJ28 and TJ68. Duration of RA was also shortest in the rituximab‐US group. Taken together, these data indicate that patients randomised to the rituximab‐US group entered the study with more severe yet shorter duration of disease than patients in the rituximab‐EU or PF‐05280586 groups.\n\nTable 1 Patient demographics and baseline disease characteristics for the PK/PD modelling analysis population\n\n\t\nPF‐05280586\n(n = 71)\n\t\nRituximab‐EU\n(n = 72)\n\t\nRituximab‐US\n(n = 71)\n\t\n\nDemographics\n\t\n\nMean age ± SD, years\n\t54.8 ± 11.7\t55.7 ± 10.2\t53.8 ± 11.8\t\n\nMale, n (%)\n\t13 (18.3)\t16 (22.2)\t19 (26.8)\t\n\nMean body weight ± SD, kg\n\t86.2 ± 22.0\t82.6 ± 19.8\t80.4 ± 21.6\t\n\nMean body surface area ± SD,\nm\n2\n\t1.9 ± 0.2\t1.9 ± 0.2\t1.9 ± 0.3\t\n\nMean disease duration since first diagnosis ± SD, years\n\t12.7 ± 8.4\t11.8 ± 8.3\t10.6 ± 8.1\t\n\nDisease characteristics, mean ± SD\n\t\n\nDAS28‐CRP\n\t5.64 ± 0.85\t5.80 ± 0.96\t6.2 ± 0.89\t\n\nHAQ‐DI\n\t1.67 ± 0.56\t1.61 ± 0.53\t1.74 ± 0.62\t\n\nSwollen joint count 28\n\t11.4 ± 5.0\t13.0 ± 6.6\t14.0 ± 6.0\t\n\nTender joint count 28\n\t14.3 ± 6.5\t15.1 ± 6.8\t18.0 ± 6.5\t\n\nSwollen joint count 66\n\t15.4 ± 8.8\t17.9 ± 10.6\t18.9 ± 8.4\t\n\nTender joint count 68\n\t22.7 ± 12.6\t23.7 ± 13.2\t29.7 ± 15.0\t\n\nCRP, mg l\n–1\n\t12.4 ± 14.9\t14.7 ± 17.6\t18.2 ± 25.1\t\n\nPhGA\n\t64.6 ± 15.3\t66.1 ± 15.5\t70.1 ± 15.6\t\n\nPatient's assessment of arthritis pain\n\t65.6 ± 17.8\t66.1 ± 21.0\t72.1 ± 18.5\t\n\nPGA\n\t67.4 ± 16.8\t67.7 ± 20.9\t74.8 ± 16.0\t\nCRP, C‐reactive protein; DAS28‐CRP, Disease Activity Score in 28 joints based on C‐reactive protein; HAQ‐DI, Health Assessment Questionnaire Disability Index; PD, pharmacodynamics; PGA, patient's global assessment of arthritis; PhGA, physician's global assessment of arthritis; PK, pharmacokinetics; SD, standard deviation.\n\nPopulation PK/PD models\nThe DAS28 dataset included 214 baseline and 1382 postbaseline observations. Model development occurred in stages proceeding from modelling DAS28 in normal scale, DAS28cfb scale, inclusion of exposure effects and lastly, inclusion of covariate effects (see Supplemental Results for additional information). Additional details, including the incorporation of between and within‐subject variability, are included in Supplemental Methods.\n\nThe final DAS28cfb model incorporated parameters related to onset (kp\ni) and maximum magnitude (PMAX\ni) of treatment effects to characterise the exponential decline in disease activity following a single course of treatment. A maximum drug effect model dependent on product concentration (Cij) included parameters representing maximum effect (Emaxi) and the concentration at which half the maximal effect is predicted (exp(θEC50)). Subject covariates and drug exposure were predictive of clinical response (Supplemental Table S1). The final DAS28cfb model predictions tracked the central tendency and distribution of DAS28cfb observations (Figure 1). In addition, inspection of plots produced for model validation indicated that the DAS28cfb model was appropriate for comparative assessment of clinical response (data not shown).\n\nFigure 1 Observed and predicted DAS28 change from baseline vs. time, by treatment. The light grey dashed lines and symbols represent individual patient response profiles, and solid lines represent the population predicted mean (PREDavg; black), observed median (red), geometric mean (orange), and individual predicted mean (iPREDavg; blue). The number of patients contributing to each time point is listed along the bottom of the x axis. DAS28, Disease Activity Score in 28 joints\n\nConcentration effects were included in the DAS28cfb model using individual predicted concentrations from the final PopPK model. A total of 2673 observations were included in the PopPK dataset and the percentage of observations below the LLOQ was low (1.5%). Other than those observations excluded that were <LLOQ, two other PK observations were excluded due to a missing sample time or missing data value. The final two‐compartment PopPK model included covariates baseline body surface area and sex on clearance and central volume, similar to previously described in patients with RA 25. The model adequately characterised the time course of drug exposure for all three products as assessed by a visual predictive check (Supplemental Figure S1) and individual prediction plots (not shown).\n\nThe ACR response dataset included 1402 observations. The effect of product treatment on probability of response over time is represented by a function consisting of parameters related to maximum effect (PMAX\ni) and onset of effect (kp\ni), similar to the DAS28cfb model. Unlike the DAS28cfb model, rituximab exposure effects could not be supported in the ACR model.\n\nCovariate effects were predictive of ACR response and lead to some interesting findings. For example, patients with higher numbers of tender joints had a lower probability of being a responder, whereas those with a higher number of swollen joints had a higher probability of response. The population mean predictions tracked the observed data for ACR20, ACR50 and ACR70 in general (Figure 2). In certain cases, the individual predictions captured the trend of the data better than population predicted (e.g. ACR20 for rituximab‐US). This may be in part due to the drop‐out characteristics since the average individual predicted (Figure 2) was only computed over the subjects who remained in the study, and therefore this method or prediction would have the same dropout characteristics as the observed data. This finding, along with inspection of plots produced for model validation (data not shown), indicated the ACR responder rate model was considered accurate for comparative assessment of clinical response.\n\nFigure 2 Observed and predicted ACR20, ACR50 and ACR70 responder rates vs. time, by treatment. Red symbols and error bars represent the observed proportion and ±2 standard errors (SE), respectively, at each time point achieving the defined ACR response criteria. Solid black lines represent the population‐predicted proportion (Pop Mean) and blue lines are mean individual predicted proportion (iPREDavg). The number of patients contributing to each time point is listed along the bottom of the x axis. ACR20/50/70, American College of Rheumatology improvement in rheumatoid arthritis of 20%/50%/70%\n\nComparative reference range\nThe comparative reference range was established from the nonlinear mixed‐effects PopPK/PD model. This range was defined as the 90% CI of the standardised difference between covariate adjusted mean predictions of an integrated clinical response (AUEC) of the two reference arms in this trial. The comparative reference range was −0.05 to 0.57 for DAS28cfb and −0.16 to 0.023 for ACR20 which were approximately similar and somewhat larger, respectively, than the range of clinical responses observed in historic trials 16, 26, 27, 28. The asymmetry (i.e. reference range not centred on zero) was a result of the use of fixed effects in the models to describe clinical response profiles for the two reference products, rather than pooling the two reference arms. The resulting reference range was considered adequate for comparative assessments based on the objective of the analysis. As an alternative approach, which emphasised the absolute differences between the covariate corrected means of the AUEC, an absolute comparative reference range (or boundary) was also established as the 90th percentile of the absolute difference between the covariate corrected means of the AUEC of the two reference arms. This boundary was 0.50 for DAS28cfb and 0.14, 0.13 and 0.099 for ACR20, ACR50 and ACR70, respectively.\n\nComparative assessments\nComparative assessment for the standardised DAS28cfb AUEC mean difference and absolute mean difference between PF‐05280586 and rituximab‐EU (0.076 and 0.083, respectively) and between PF‐05280586 and rituximab‐US (0.32 and 0.33, respectively) showed that the differences were within the comparative reference range and absolute comparative reference range (Figure 3). Similarly, the ACR20 AUEC differences between PF‐05280586 and rituximab‐ EU (−0.016 and 0.012, respectively) and between PF‐05280586 and rituximab‐US (−0.084 and 0.077, respectively; Figure 4) were within the reference range and absolute reference range. This was also confirmed for ACR50 and ACR70 using the absolute mean differences and their reference ranges, respectively (Supplemental Figure S2).\n\nFigure 3 Comparative assessment between PF‐05280586 and two rituximab comparators for DAS28cfb normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for DAS28cfb. AUEC, area under the effect curve; DAS28cfb, Disease Activity Score in 28 joints change from baseline\n\nFigure 4 Comparative assessment between PF‐05280586 and two rituximab comparators for ACR20 responder rates normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (single vertical dashed red line) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for ACR20. ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; AUEC, area under the effect curve\n\nCase–control analysis\nPrior to matching, several subcomponents of DAS28 and ACR response rate were statistically different between reference groups as well as between the pooled reference group (rituximab‐EU/US) and PF‐05280586 group (Supplemental Table S2). A propensity score model, which included two subcomponents, SJ66 and patient's assessment of pain, was sufficient to balance all disease characteristics (including DAS28; Supplemental Table S2). The resulting subset was ~70% of the original dataset. The resulting mean DAS28cfb and ACR20 profiles in this subset of patients showed lack of an effect due to imbalance in baseline patient disease characteristics among all treatment groups compared with those in the original dataset (Figure 5).\n\nFigure 5 Clinical response profiles for three treatment groups before (left panels) and after (right panels) matching, based on swollen joint counts and patient's assessment of pain. Points represent mean (DAS28cfb, top) or proportion (ACR20, bottom). ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; DAS28cfb, Disease Activity Score in 28 joints change from baseline\n\nDiscussion\nWe describe a PopPK/PD approach for comparative assessments of clinical responses between PF‐05280586, a proposed biosimilar to rituximab, and two rituximab products (references) in patients with RA. This approach was designed to take advantage of multiple repeated measurements for each clinical end point and variability observed between the two reference products used in the PK study. A procedure for determining the criteria as to whether a meaningful difference between PF‐05280586 and reference products was observed in the study was prospectively defined, providing a framework for the comparative assessments. Based on these criteria, any mean difference within the reference range would not be considered meaningful. Establishing the reference range relied on the assumption that both reference products had equivalent potency and that, given PK similarity was established, any difference in clinical responses observed between the two references in a single trial are due to study design attributes (not product‐related), such as between‐subject variability or imperfect randomization in baseline disease characteristics among treatment groups. Thus, emphasis is placed on the distribution of differences between references that may be expected between two similar products in a PK trial setting with ~70 subjects per arm. In comparison to historical data extracted from several randomised clinical trials, reference ranges established in this trial are similar in size to those observed across trials for DAS28 but somewhat larger than those for ACR20 16, 26, 27, 28.\n\nThe traditional approach – using ACR clinical response rate at the end of a specified period as the primary end point in randomised clinical trials to distinguish active treatment from placebo – may not be optimal for the biosimilarity assessment between two active treatments especially when the clinical dose is located on the plateau of the dose response curve 22, 29. This limitation was a motivating factor for utilizing the repeated clinical response measurements for the model‐based comparative assessments, along with assessment of another clinical response endpoint (i.e. DAS28), in an attempt to improve detection of a potential difference and add to the totality of evidence for demonstration of biosimilarity. Integrating all PK/PD (clinical response) measurements over time using the model‐based approach allowed examination of onset of effect and magnitude of response along with precise estimation of AUEC, a parameter of interest for clinical comparability assessments consistent with the FDA draft guidance on clinical pharmacology data to support demonstration of biosimilarity 9.\n\nIn this study, an underlying imbalance in the rituximab‐EU and rituximab‐US groups was evident from baseline patient disease characteristics. To adequately characterise response profiles for each group, separate fixed‐effects were estimated for each reference group, in addition to inclusion of covariates to account for the imbalance. The aim was to evaluate whether treatment differences could be explained or predicted by the covariates through the imbalance between groups. Therefore, the simultaneous estimation approach was preferable to forward selection of covariates which may introduce bias in the estimated values 30, 31. Incorporation of covariates in the models assuming a pooled rituximab‐EU/US population (data not shown) did not account for all the imbalance, indicating unmeasured covariates also may have contributed to the underlying imbalance. In addition to the pooling approach, an attempt to incorporate group‐specific random effects to provide correlation within the groups was conducted. This confirmed that it was not possible to estimate a precise between‐group variability term with the small number of groups to characterise the remaining difference between the two reference products after inclusion of covariates in the model. As may be expected, comparative assessments between two reference products conducted with fixed effects resulted in an asymmetric comparison. That is, the distribution of mean estimated differences between two reference products is shifted, resulting in a nonzero mean. Details of this particular finding, while insightful, may not be easily understood without evaluation of simulation of various hypothetical scenarios. An alternative perspective, which is included in our analysis, was to evaluate each assessment using absolute difference. Since the emphasis of similarity is on the magnitude of difference, the absolute difference is consistent with the objectives of the given analysis and offered an intuitive interpretation of the analysis results. Lastly, imbalances in baseline disease characteristics, which tend to occur in PK trial settings, can be addressed to a great extent in the mixed‐effect modelling framework through a typical covariate analysis. In this regard, the models developed in this analysis included the individual components of baseline disease activity and elucidated potential confounding factors. In particular, the ACR model indicated that patients with a higher swollen joint count had a higher probability of being an ACR responder, while those with a higher tender joint count had a lower probability. As others have described, joint tenderness might indicate chronification of the pain reaction rather than ongoing inflammation and could therefore be a confounding factor 32. That is, a disconnection between the number of swollen and tender joints may appear in RA patients who have developed widespread pain syndromes or other hyperalgesic conditions 32 and consequently could result in somewhat different populations with respect to their potential to respond to treatment.\n\nStill, as found in this analysis, there may be unaccounted imbalances in the data presumably due largely to the randomization with small sample sizes and no stratification based on disease activity. In verifying this, an orthogonal approach using case–control analysis to match patients based on one or more variables may be useful, as described for an exposure–response analysis 33. This approach is often used to account for imbalance in nonrandomised studies and typically with much larger sample sizes. Applied here, this approach helped identify two important measures of disease activity, swollen joint count and patient's assessment of pain, which, when used for matching, resulted in balanced baseline disease activity among treatment groups. The resulting balanced groups all had similar clinical response profiles.\n\nIn conclusion, no point estimates of mean differences were found outside the reference ranges for either DAS28 or ACR20 scores. Furthermore, the estimated probabilities that the predicted differences for the given comparisons, PF‐05280586 vs. rituximab‐EU or PF‐05280586 vs. rituximab‐US, lie outside the boundaries of the respective reference ranges of absolute differences are low. Our analysis provided a case study where a model‐based PK/PD approach was utilised for biosimilarity assessment using clinical response data from the PK similarly study comparing a proposed biosimilar against two reference products. The results may therefore be used as a PK/PD demonstration of no clinically meaningful differences in support of overall biosimilarity determination. This case study offers an example for additional applications of clinical pharmacology studies and approaches aimed for efficient biosimilar development that are essential for improving patient access to the important, often lifesaving, biologic therapies.\n\nCompeting Interests\nAll authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (http://www.icmje.org/coi_disclosure.pdf) (available on request from the corresponding author) and declare the following financial relationships with organizations that might have an interest in the submitted work in the previous 3 years: BG, LAM, DY, RL and XM are employees of Pfizer Inc., JHW, MLZ, and GSG were employees of Pfizer Inc at the time of the study, MMH and J‐CB were paid consultants of Pfizer Inc.\n\n\nWe acknowledge the investigators and patients who contributed to this study. We thank Jian Du, Dian Xu and Stuart Pearce for preparation of NONMEM datasets. We thank Michael Amantea for helpful advice. This study was funded by Pfizer Inc. Editorial assistance was provided by Christina McManus, PhD, of Engage Scientific Solutions and funded by Pfizer.\n\nContributors\nJHW and XM designed the research. J‐CB, BG, LAM, GSG, DY, RL, JHW, MMH, MLZ, K‐HL and XM performed the research. MMH, JHW, MLZ, K‐HL and XM analysed the data. JHW and XM wrote the manuscript.\n\nSupporting information\n\nTable S1 Parameter estimates for Disease Activity Score in 28 Joints change from baseline and American College of Rheumatology responder rate models.\n\n\nTable S2 Patient demographics and baseline disease characteristics for the pharmacokinetic/pharmacodynamic modelling analysis population before and after propensity score matching.\n\n\nFigure S1 Visual predictive check of the rituximab pharmacokinetic model.\n\n\nFigure S2 Comparative assessment between PF‐05280586 and two rituximab comparators for ACR50 and ACR70 responder rates normalised area under effect curves.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nSouthan \nC \n, \nSharman \nJL \n, \nBenson \nHE \n, \nFaccenda \nE \n, \nPawson \nAJ \n, \nAlexander \nSP \n, et al.\nThe IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands . 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J Clin Pharmacol \n2013 ; 53 : 160 –166 .23436261\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0306-5251", "issue": "82(6)", "journal": "British journal of clinical pharmacology", "keywords": "Biosimilar; pharmacodynamics; pharmacokinetics", "medline_ta": "Br J Clin Pharmacol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "7503323", "other_id": null, "pages": "1568-1579", "pmc": null, "pmid": "27530379", "pubdate": "2016-12", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "17127262;23982986;18571968;23436261;27530379;25353186;26909489;20488885;19626001;22048227;1575785;23436260;15951469;22318617;26650438;15201414;16947627;18058203;20635122;16649186;20699241;26464438", "title": "Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab.", "title_normalized": "comparative assessment of clinical response in patients with rheumatoid arthritis between pf 05280586 a proposed rituximab biosimilar and rituximab" }	[ { "companynumb": "MX-ROCHE-1410426", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" } ], "patientagegroup": null, "patientonsetage": "20", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "77.5", "reaction": [ { "reactionmeddrapt": "Thrombocytopenic purpura", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130428" } }, "primarysource": { "literaturereference": ", HUTMACHER M, ZIERHUT M, BECKER J-C, GUMBINER B, SPENCER-GREEN G, MELIA L, LIAO K-H, SUSTER M, YIN D, LI R AND MENG X. COMPARATIVE ASSESSMENT OF CLINICAL RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS BETWEEN PF-05280586, A PROPOSED RITUXIMAB BIOSIMILAR, AND RITUXIMAB. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2016;:1-12.", "literaturereference_normalized": "comparative assessment of clinical response in patients with rheumatoid arthritis between pf 05280586 a proposed rituximab biosimilar and rituximab", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20161004", "receivedate": "20140821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10397728, "safetyreportversion": 7, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170206" } ]
{ "abstract": "Amiodarone is a common antiarrhythmic drug that is utilised in clinical practice and is associated with pulmonary toxicity. The most common form of pulmonary complication is interstitial pneumonitis which is treated with discontinuation of amiodarone and initiation of corticosteroids. Amiodarone-induced pulmonary eosinophilia is a rare complication of amiodarone therapy, with blood and pulmonary eosinophilia the predominant features. During the COVID-19 era, the incidence of delay in treatment of pulmonary pathology is also delayed due to the effort of excluding COVID-19 infection. Here we report a case of a 64-year-old man who developed eosinophilic pneumonia after initiation of amiodarone therapy, and the investigations required to exclude other forms of pulmonary toxicity. We also reviewed the effect of COVID-19 testing in the management of patients presenting with respiratory distress.", "affiliations": "Department of Cardiology, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.;Department of Respiratory Medicine, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.;Department of Cardiology, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.", "authors": "Azraai\|Meor\|M\|;McMahon\|Marcus\|M\|;Dick\|Ronald\|R\|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone", "country": "United States", "delete": false, "doi": "10.31083/j.rcm.2021.01.267", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-6550", "issue": "22(1)", "journal": "Reviews in cardiovascular medicine", "keywords": "Amiodarone; Amiodarone-induced pulmonary toxicity; COVID-19; Corticosteroids; Pulmonary eosinophilia", "medline_ta": "Rev Cardiovasc Med", "mesh_terms": "D000542:Alveolitis, Extrinsic Allergic; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000086382:COVID-19; D000086742:COVID-19 Testing; D057210:Delayed Diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "100960007", "other_id": null, "pages": "181-184", "pmc": null, "pmid": "33792260", "pubdate": "2021-03-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Case report of amiodarone-associated allergic pneumonitis amidst the COVID-19 pandemic.", "title_normalized": "case report of amiodarone associated allergic pneumonitis amidst the covid 19 pandemic" }	[ { "companynumb": "AU-MYLANLABS-2021M1039380", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Atrial fibrillation", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "1200 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Atrial fibrillation", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilic pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory fatigue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Azraai M, McMahon M, Dick R. Case report of amiodarone-associated allergic pneumonitis amidst the COVID-19 pandemic. Rev-Cardiovasc-Med 2021;22(1):181-184.", "literaturereference_normalized": "case report of amiodarone associated allergic pneumonitis amidst the covid 19 pandemic", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220303", "receivedate": "20210708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19506954, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" } ]
{ "abstract": "A 74-year-old woman with a week-long history of cold symptoms was diagnosed with Lemierre syndrome that involved her left external jugular vein.\n\n\n\nThe patient was successfully treated with 4 weeks of antibiotics and anticoagulant treatment. Typical cases of Lemierre syndrome involve only the internal jugular vein. The external jugular vein is anatomically distant from the pharyngolaryngeal space and usually does not receive blood or lymphatic flow from there. Thus, Lemierre syndrome ordinarily does not involve the external jugular vein and clinical characteristics of external jugular vein-involving Lemierre syndrome have not been uncovered, mainly due to its rarity. Based on our review, it would not much differ from those of typical cases.\n\n\n\nConsidering the potential severity and mortality, more attention should be paid to this potentially fatal disease that may demonstrate atypical manifestation, as shown in this case. Accumulation of cases would be needed for further understanding.", "affiliations": "Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyama Okayama Japan.;Department of Pharmacy Tsuyama Central Hospital Tsuyama Okayama Japan.;Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyama Okayama Japan.", "authors": "Hagiya\|Hideharu\|H\|;Haruki\|Yuto\|Y\|;Otsuka\|Fumio\|F\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/ams2.61", "fulltext": null, "fulltext_license": null, "issn_linking": "2052-8817", "issue": "2(1)", "journal": "Acute medicine & surgery", "keywords": "External jugular vein (EJV); Fusobacterium; Lemierre syndrome; jugular vein suppurative thrombophlebitis; septic pulmonary emboli (SPE)", "medline_ta": "Acute Med Surg", "mesh_terms": null, "nlm_unique_id": "101635464", "other_id": null, "pages": "64-68", "pmc": null, "pmid": "29123694", "pubdate": "2015-01", "publication_types": "D002363:Case Reports", "references": "17308690;10371324;16020900;12441902;9796654;464215;15192164;10326820;24436600;18330604", "title": "Lemierre syndrome involving external jugular vein.", "title_normalized": "lemierre syndrome involving external jugular vein" }	[ { "companynumb": "JP-TEVA-2017-JP-836089", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "89081", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSES, 3 G EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUSOBACTERIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN/SULBACTAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypercoagulation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lemierre syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Glucose tolerance impaired", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Laryngeal inflammation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA H, HARUKI Y, OTSUKA F. LEMIERRE SYNDROME INVOLVING EXTERNAL JUGULAR VEIN. ACUTE-MED-SURG 2015?2(1):64-68.", "literaturereference_normalized": "lemierre syndrome involving external jugular vein", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180107", "receivedate": "20171227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14329454, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "JP-MYLANLABS-2017M1078035", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSES, 3 G EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUSOBACTERIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPI BIS PLUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypercoagulation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lemierre syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephritis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Glucose tolerance impaired", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Laryngeal inflammation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA H, HARUKI Y, OTSUKA F. LEMIERRE SYNDROME INVOLVING EXTERNAL JUGULAR VEIN. ACUTE-MED-SURG 2015;2(1):64-68.. 2015;2(1):64-68", "literaturereference_normalized": "lemierre syndrome involving external jugular vein", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171221", "receivedate": "20171221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14314939, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]
{ "abstract": "OBJECTIVE\nTo assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies.\n\n\nMETHODS\nRetrospective single-centre study of 25 patients with refractory TAK.\n\n\nRESULTS\nPatients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2-84)) and 9 with ETA (median 28 months (range 4-82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer.\n\n\nCONCLUSIONS\nIn this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.", "affiliations": "Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH 44106, USA. molloye@ccf.org", "authors": "Molloy\|E S\|ES\|;Langford\|C A\|CA\|;Clark\|T M\|TM\|;Gota\|C E\|CE\|;Hoffman\|G S\|GS\|", "chemical_list": "D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1136/ard.2008.093260", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4967", "issue": "67(11)", "journal": "Annals of the rheumatic diseases", "keywords": null, "medline_ta": "Ann Rheum Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D018124:Receptors, Tumor Necrosis Factor; D012008:Recurrence; D012189:Retrospective Studies; D013625:Takayasu Arteritis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0372355", "other_id": null, "pages": "1567-9", "pmc": null, "pmid": "18677012", "pubdate": "2008-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up.", "title_normalized": "anti tumour necrosis factor therapy in patients with refractory takayasu arteritis long term follow up" }	[ { "companynumb": "US-JNJFOC-20170527310", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "RANE (4-10 MG/KG) ADMINISTERED AT A MEDIAN INTERVAL OF 6 WEEKLY (RANGE 4-8 WEEKLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "TAKAYASU^S ARTERITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Breast cancer", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MOLLOY ES, LANGFORD CA, CLARK TM, GOTA CE, HOFFMAN GS. ANTI-TUMOUR NECROSIS FACTOR THERAPY IN PATIENTS WITH REFRACTORY TAKAYASU ARTERITIS: LONG-TERM FOLLOW-UP. ANN RHEUM DIS 03-AUG-2008;67:1567-1569.", "literaturereference_normalized": "anti tumour necrosis factor therapy in patients with refractory takayasu arteritis long term follow up", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170530", "receivedate": "20170530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13592697, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-JNJFOC-20170527333", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "5 MG/KG RANGE (4-10 MG/KG) ADMINISTERED AT A MEDIAN INTERVAL OF 6 WEEKLY (RANGE 4-8 WEEKLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "TAKAYASU^S ARTERITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Histoplasmosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MOLLOY ES, LANGFORD CA, CLARK TM, GOTA CE, HOFFMAN GS. ANTI-TUMOUR NECROSIS FACTOR THERAPY IN PATIENTS WITH REFRACTORY TAKAYASU ARTERITIS: LONG-TERM FOLLOW-UP. ANN RHEUM DIS 2008;67:1567-1569.", "literaturereference_normalized": "anti tumour necrosis factor therapy in patients with refractory takayasu arteritis long term follow up", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170530", "receivedate": "20170530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13592698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "BACKGROUND\nThe development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good's syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.\n\n\nMETHODS\nA 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.\n\n\nCONCLUSIONS\nIt is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.", "affiliations": "Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan. lacote19thg@gmail.com.;Department of Thoracic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.", "authors": "Ueno\|Tatsuya\|T\|http://orcid.org/0000-0002-6212-0265;Sato\|Nobuyuki\|N\|;Kon\|Tomoya\|T\|;Haga\|Rie\|R\|;Nunomura\|Jin-Ichi\|JI\|;Nakamichi\|Kazuo\|K\|;Saijo\|Masayuki\|M\|;Tomiyama\|Masahiko\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-018-1041-4", "fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 104110.1186/s12883-018-1041-4Case ReportProgressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review http://orcid.org/0000-0002-6212-0265Ueno Tatsuya +81 17 726 8111lacote19thg@gmail.comtatsuya_ueno@med.pref.aomori.jp 1Sato Nobuyuki nobuyuki_sato@med.pref.aomori.jp 2Kon Tomoya tk10608pc@nifty.com 1Haga Rie rie_haga@med.pref.aomori.jp 1Nunomura Jin-ichi Jin-ichi_Nunomura@med.pref.aomori.jp 1Nakamichi Kazuo nakamich@nih.go.jp 3Saijo Masayuki masaijo@nih.go.jp 3Tomiyama Masahiko masahiko_tomiyama@med.pref.aomori.jp 11 0000 0004 0378 7152grid.413825.9Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551 Japan 2 0000 0004 0378 7152grid.413825.9Department of Thoracic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan 3 0000 0001 2220 1880grid.410795.eDepartment of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan 10 4 2018 10 4 2018 2018 18 3721 11 2017 27 3 2018 © The Author(s). 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good’s syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.\n\nCase presentation:\nA 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.\n\nConclusions\nIt is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.\n\nKeywords\nProgressive multifocal leukoencephalopathyGood’s syndromeMyasthenia gravisThymomaImmunodeficiencyJC virushttp://dx.doi.org/10.13039/501100001691Japan Society for the Promotion of Science17K09768Nakamichi Kazuo http://dx.doi.org/10.13039/501100003478Ministry of Health, Labour and WelfareH29-Nanchitou (Nan)-Ippan-036Saijo Masayuki issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nProgressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus (JCV) [1]. The development of PML is associated with severe cellular immunosuppression e.g., human immunodeficiency virus (HIV) infection, and immunosuppressive therapy, including natalizumab and other monoclonal antibodies, fingolimod, and dimethyl fumarate [2].\n\nPatients with thymoma often also have an autoimmune disease, such as myasthenia gravis (MG) [3]. Good’s syndrome (GS), also referred to as thymoma with immunodeficiency, is a rare immunodeficiency syndrome related to thymoma, characterized by hypogammaglobulinemia, low or absent B cells, CD4+ lymphopenia, and reversal of the CD4/CD8 ratio [4, 5]. GS thus involves not only humoral, also cellular immunosuppression [4, 5]. The incidence of hypogammaglobulinemia in patients with thymoma is 6%–11%, while GS occurs in 7% of patients with primary antibody deficiency referred to a chest clinic, and is the underlying cause of immunodeficiency in 1%–2% of patients with primary antibody deficiency receiving immunoglobulin replacement therapy [4, 6]. MG has been identified in 9.1%–15.7% of patients with GS [4, 5].\n\nTo the best of our knowledge, eight cases of PML with thymoma have been reported in the literature (Table 1) [7–14], though GS was confirmed in only three of these eight cases [11, 12, 14]. In the case of PML related to thymoma, it may be difficult to judge if the immunodeficiency is caused by chemotherapy for the thymoma, by GS caused by the thymoma itself, by immunosuppressive therapy for MG, or by a combination of these. The neurological symptoms improved in one patient with PML related to immunosuppressive therapy for MG, complicated with thymoma, following a reduction of immunotherapy for PML (Table 1) [10]. It is therefore important to identify the cause of the immunodeficiency responsible for PML, to enable the development of an appropriate treatment strategy. We herein report a patient with invasive thymoma who developed PML, who also had chemotherapy-induced immunodeficiency and GS due to an invasive thymoma.Table 1 Clinical features of patients with progressive multifocal leukoencephalopathy related to thymoma\n\nReference\tAge\tSex\tCauses of immunodeficiency\tTime\tTreatment ofthymoma\tJC virus\nin the CSF\tCD19+ B cell\n(cells/μL)\tCD4/CD8\tCD4+ T cell\n(cells/μL)\tCD8+ T cell\n(cells/μL)\tIg level\n(mg/dL)\tPML\nTreatment\tPrognosis\tSurvival\nperiod\t\n[14]\t65\tF\tGood’s syndrome\t0\tSR\t>1million\ncopies/mL\tNo detectable\t0.66\n(1.13–3.93)\tNR\tNR\tIgG: 570 (670–1450)\nIgA: 22 (88–450)\nIgM: 22 (27–210)\tMirtazapine\nMefloquine\tDeath\tProbably\n5–6 M\t\n[13]\t39\tM\tChemotherapy for thymoma\t10 Y\tSR + CT\t9,200\ngEq/μL\t1 (100–800)\t0.2\n(0.9–2.8)\t19\n(450–1500)\t113\n(250–1000)\tNR\tCidofovir\tDeath\tNR\t\n[12]\t79\tF\tGood’s syndrome\t8 Y\tSR\t9,258\npairs/mL\tAbsent\t1.5\t648\t425\tIgG: 619 (700–1600)\nIgA: <25 (70–400)\nIgM: <18 (40–250)\tCidofovir\tDeath\t5 M\t\n[11]\t58\tM\tGood’s syndrome\t5 M\tSR\t810\ncopies/mL\tNR\t0.6\n(0.8–2.4)\tNR\tNR\tIgM: 31 (40–300)\tCidofovir\nRisperidone\nIVIg\tAlive\tAt least 11 M\t\n[10]\t44\tF\tImmunosuppressive therapy for MG\t2 M\tSR\tPositive\tNR\tNR\tNR\tNR\tNR\tReduction of immunotherapy\tAlive\tAt least 19 M\t\n[9]\t58\tM\tChemotherapy\nGood’s syndrome?\t9 Y\tRT + CT\tNR\tNR\tNR\tNR\tNR\tNR\tCytrabine\tDeath\t13 W\t\n[8]\t41\tF\tImmunosuppressive therapy for MG\t29 Y\tRT + SR\tNR\tNR\tNR\tNR\tNR\tNR\tReduction of immunotherapy\tDeath\t6 W\t\n[7]\t39\tF\tImmunosuppressive therapy for MG\nGood’s syndrome?\t3 Y\tRT\tNR\tNR\tNR\tNR\tNR\tNR\tNone\tDeath\t5 M\t\nPresent case\t47\tF\tGood’s syndrome\nChemotherapy\t23 Y\tRT + SR + CT\t6,283,000\ncopies/mL\t3\t0.6\t11\t19\tIgG: 282 (870–1700)\nIgA: 58 (110–410)\nIgM: 15 (35–220)\tMirtazapine\nMefloquine\nIVIg\tDeath\t3 M\t\nTime = period from the diagnosis of thymoma to the onset of PML. Numbers in parentheses indicate the reference range. Patients in references [9, 10] survived for at least 11 and 19 months, respectively, but their subsequent prognosis was unknown. Abbreviations. CSF: cerebrospinal fluid; CT: chemotherapy; IVIg: intravenous immunoglobulin; M: months; MG: myasthenia gravis; NR: not reported; PML: progressive multifocal leukoencephalopathy; RT: radiation therapy; SR: surgical resection; W: weeks; Y: years\n\n\n\nCase presentation\nA 47-year-old Japanese woman with aphasia and gait difficulty was admitted for the evaluation of a brain magnetic resonance imaging (MRI) abnormality. She had gradually developed aphasia and gait difficulty 2 months before admission. Her medical history included an invasive thymoma diagnosed at 24 years old, MG (Myasthenia Gravis Foundation of America clinical classification IIa) at 35 years old, cryptococcal meningoencephalitis at 36 years old, and erythrodermic psoriasis at 46 years old. The time course of her medical history and treatments are shown in Fig. 1. Ptosis and limb weakness, as MG symptoms, had completely recovered. She demonstrated chemotherapy-induced immunosuppression, and the invasive thymoma (Masaoka stage IVB) was refractory to shrinkage by multiple chemotherapies. The invasive thymoma had also seeded intraperitoneally. She had received her last chemotherapy (cyclophosphamide, 500 mg; doxorubicin, 50 mg; cisplatin, 50 mg) 16 months before admission, and had been taking prednisolone (12.5 mg/day) from 44 years of age. Her family history was unremarkable.Fig. 1 Medical history and treatment course. ADR: adriamycin; CBDCA: carboplatin; CDDP: cisplatin; CM: cryptococcal meningoencephalitis; CPA: cyclophosphamide; DOX: doxorubicin; EP: erythrodermic psoriasis; MG: myasthenia gravis; PTX: paclitaxel; PSL: prednisolone; RT: radiation therapy; S-1: tegafur/gimeracil/oteracil potassium; SR: surgical resection of thymoma; VCR: vincristine; VDS: vindesine\n\n\n\nOn admission, her body weight was 39.5 kg and she was 151.7 cm tall (body mass index of 17.2 kg/m2). Her vital signs were normal and her Glasgow coma scale score was 12 (E4V2M6). Physical examination revealed widespread erythema with scaling and exfoliation of the skin due to erythrodermic psoriasis, and an invasive thymoma in the left lower chest wall. She had a central venous port for chemotherapy in her left upper chest wall. Neurological examination revealed motor aphasia and central facial weakness on the right side. Barré’s sign for the upper extremities and Mingazzini’s sign for the lower extremities were negative. Finger-to-nose and heel-to-knee tests demonstrated no abnormalities. Bilateral deep tendon reflexes were normal, but bilateral plantar responses were extensor.\n\nLaboratory studies showed the following results: hematocrit, 32.6%; hemoglobin, 10.7 g/dL; red blood cell count, 3.74 × 106/μL; mean corpuscular volume, 87.1 fL; platelet count, 22.7 × 104/μL; and white blood cell count, 8.2 × 103/μL, with 0.9% lymphocytes (74 cells/μL). Lymphocyte subgroups were as follows: CD4, 14.9% (normal range 25.0%–54.0%); CD8, 25.0% (normal range 2.0%–56.0%); CD4/CD8 ratio, 0.6; CD19, 0.4% (normal range 5.0%–24.0%); and CD20, 1.1% (normal range 3.0%–20.0%). Her total IgG level was 282 mg/dL (normal range 870–1700 mg/dL), IgA level was 58 mg/dL (normal range 110–410 mg/dL), and IgM level was 15 mg/dL (normal range 35–220 mg/dL). Serology for HIV type 1/2, human T-lymphotropic virus type 1, Candida, Aspergillus, Toxoplasma, and Mycobacterium tuberculosis were all negative. Anti-acetylcholine receptor (AchR) antibodies were positive (0.4 nmol/L: normal range < 0.3 nmol/L). Cerebrospinal fluid (CSF) analysis revealed a normal cell count, protein, and glucose, but an elevated IgG index (1.1) and elevated myelin basic protein levels (238 pg/mL). Oligoclonal bands and CSF cytology were negative. CSF cultures for bacteria, fungi, and M. tuberculosis were negative. CSF polymerase chain reaction (PCR) tests for M. tuberculosis, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus were all negative, but CSF real-time PCR for JCV was positive, showing 6,283,000 copies/mL. Brain MRI showed hyperintense lesions in the left frontal white matter on T2-weighted images and fluid-attenuated inversion recovery images (Fig. 2a, b). These lesions were hypointense without contrast enhancement on T1-weighted images (Fig. 2c, d). Diffusion-weighted images (DWI) demonstrated a hyperintense lesion in the margin of left frontal white matter (Fig. 2e). Arterial spin labeling revealed hyperperfusion in the DWI hyperintense lesion (Fig. 2f). Magnetic resonance spectroscopy showed a decrease in N-acetylaspartate and increased lactate in the lesions (Fig. 3). Thallium-201 single photon emission computed tomography revealed no uptake in the lesions (Fig. 4). Based on the results of clinical features, imaging findings, and CSF PCR for JCV, the patient was finally diagnosed with non-HIV-related PML due to chemotherapy-induced immunodeficiency and GS [4, 15].Fig. 2 Brain magnetic resonance imaging on admission (a-e) and at 30 days after admission (f). T2-weighted images (a) and fluid-attenuated inversion recovery images (b) show hyperintense lesions in the left frontal white matter. These lesions were hypointense on T1-weighted images (c). There was no enhancement on gadolinium-enhanced T1-weighted images (d). Diffusion-weighted images (DWI) demonstrated a hyperintense lesion in the margin of the left frontal white matter (e). Arterial spin labeling revealed hyperperfusion in the DWI hyperintense lesion (f)\n\nFig. 3 Magnetic resonance spectroscopy (MRS) and diffusion-weighted images (DWI) at 30 days after admission. Representative locations selected for MRS (a). MRS showed a decrease in N-acetylaspartate and increased lactate in the DWI hyperintense lesion (b, c)\n\nFig. 4 Thallium-201 single photon emission computed tomography at 11 days after admission. Early (a) and delayed (b) scans demonstrated no uptake in the lesions\n\n\n\nMonthly intravenous immunoglobulin (IVIg) therapy for hypogammaglobulinemia was started 10 days after admission. After the diagnosis of non-HIV-related PML, mirtazapine 15 mg/day was started 24 days after admission, and oral mefloquine 275 mg/day was also started for 3 days on day 25, followed by 275 mg once weekly. We also tapered her prednisolone to 10 mg/day on day 44. She had no deterioration of neurological symptoms indicating immune reconstitution inflammatory syndrome. However, she developed central venous port-related infections with no improvement of neurological symptoms, and received antibiotic and antifungal treatments on day 39. Although we tried to remove the central venous port, it could not be withdrawn without a risk of vascular injury. The above treatments were continued, but the patient unfortunately died of sepsis due to Candida albicans and Staphylococcus epidermis, as determined by blood culture on day 46.\n\nDiscussion and conclusions\nWe present a patient with invasive thymoma-associated PML who also had chemotherapy-induced immunodeficiency and GS due to the invasive thymoma. This case demonstrates two important points: (1) it is necessary to consider the possibility of GS in patients with PML related to thymoma; and (2) neurologists should keep in mind the risk of PML in MG patients with thymoma, even if their MG symptoms are in remission.\n\nAccording to our literature review, the possible causes of immunodeficiency in patients with thymoma-related PML include GS, chemotherapy-induced immunodeficiency, and immunosuppressive therapy for MG (Table 1). Our patient had CD4+, CD8+, and CD19+ lymphopenia, and hypogammaglobulinemia, which are characteristics of GS [4, 5]. These results suggest that this patient had GS. GS with PML has been reported in three previous cases, none of whom received chemotherapy for thymoma [11, 12, 14]; however, our patient had received repeated chemotherapy for invasive thymoma (Table 1). We were unable to judge if another two cases had GS, because their immunological statuses were not reported [7, 8]. Chemotherapeutic agents, such as cyclophosphamide, doxorubicin, vincristine, and methotrexate, can cause lymphopenia, including decreases in CD19+ B cells, CD4+ and CD8+ T cells, and decreased IgM levels with normal IgG levels [16]. The recovery periods for B cells and CD8+ T cells after chemotherapy are 1–3 months and 3–6 months, respectively [17–19]. The recovery of CD4+ T cells 6 months after completion of cytotoxic chemotherapy is inversely related to age for children younger than approximately 15 years, whereas persistent depletion is observed in older patients [20]. Given that a year had passed after the last chemotherapy in the current case, it was possible that her B and CD8+ T cells might have recovered, but that was not the case, while all immunoglobulin subclasses were also decreased. The patient’s age suggests that the decrease of CD4+ T cells may have been caused by her chemotherapy. There are currently no established diagnostic criteria or specific biomarkers for GS, and it is diagnosed on the basis of the existence of thymoma, hypogammaglobulinemia, low or absent B cells, CD4+ lymphopenia, and reversal of the CD4/CD8 ratio [4, 5]. Our patient with invasive thymoma had decreased B and CD8+ T cells, and hypogammaglobulinemia, even after considering chemotherapy, and we therefore considered the possibility of GS in addition to chemotherapy-induced immunodeficiency, resulting in severe humoral and cellular immunosuppression. To the best of our knowledge, this is the first reported case of PML with concurrent MG and GS against a background of thymoma. It is therefore necessary to judge patients with various possible causes of immunodeficiency, including chemotherapy, comprehensively, rather than assuming that chemotherapy-induced immunodeficiency is the cause.\n\nThere have been two reported cases of comorbid PML with MG (Table 1), neither of whom received chemotherapy. There was no description of any lymphopenia or hypogammaglobulinemia [8, 10] (Table 1), but their MG symptoms were presumably severe, because they received high-dose prednisolone and azathioprine for symptom control [8, 10]. It is therefore possible that this immunosuppressive therapy may have triggered the onset of PML. We were unable to judge if these two cases had GS. In the current case, PML occurred even when MG was in remission. However, this patient had severe humoral and cellular immunosuppression, and her MG symptoms may thus have improved. Neurologists should therefore consider the possibility of PML in patients with MG related to thymoma who experience progressive exacerbation of neurological symptoms, regardless of the severity of MG symptoms, and should evaluate the patient’s immunological status accordingly, including complete blood count, quantitative immunoglobulins, and B cell/T cell subsets. Regarding the need for immunological evaluations of MG patients without thymoma at the initial presentation, it is advisable to evaluate the immunological status of such patients if their neurological symptoms or anti-AchR antibody values deteriorate, given that a thymoma may be detected subsequently [21].\n\nIt is also necessary to consider treating GS to prevent the development of PML; however, this is challenging because there is currently no established treatment for GS [6], though thymectomy, radiotherapy, combination chemotherapy, immunosuppressive therapy, plasmapheresis, and splenectomy are all possible treatment options [4]. Squintani et al. reported on a patient with PML who had normal CD4+ and CD8+ T cells and hypogammaglobulinemia, indicating humoral but not cellular immunodeficiency [12]. Because PML is associated with severe cellular immunosuppression [2], hypogammaglobulinemia itself does not usually result in reactivation of JCV. Although Squintani et al.’s case might also have had cellular immunodeficiency, treatment of GS-related hypogammaglobulinemia by immunoglobulin replacement therapy may be considered for PML prevention.\n\nThe reported period from the diagnosis of thymoma to the onset of PML is 0–29 years (Table 1). Two patients with relatively short periods from thymoma diagnosis to PML onset survived [10, 11], including one patient with MG who received a reduction of immunotherapy for PML [10], and a patient with GS who received cidofovir and risperidone for PML and IVIg for GS [11]. No quantitative analyses were performed in the patient with MG [10], but the patient with GS had a low JCV level (810 copies/mL) [11]. In the case of thymoma diagnosis with simultaneous onset of PML, the patient with GS had a high JCV level (> 1 × 106 copies/mL) and was treated with mirtazapine and mefloquine, but probably died within 5–6 months [14]. Patients with a low CSF JCV level were found to survive longer than patients with a higher JCV level [22], though the median survival of patients with non-HIV-related PML was only 3 months [23]. In the current case, the period from thymoma diagnosis to PML onset was 24 years. This patient had a high JCV level (6,283,000 copies/mL) and received mirtazapine, mefloquine, and IVIg, but died of sepsis after 3 months. JCV levels may thus be a better prognostic marker than time from thymoma diagnosis to PML onset in patients with PML related to thymoma; however, the rarity of reported cases means that this possibility needs to be evaluated in other cases.\n\nIn summary, we present a patient with invasive thymoma-associated PML who also had chemotherapy-induced immunodeficiency and GS due to thymoma. This case highlights the need to consider the possibility of immunodeficiency caused by to GS in patients with PML related to thymoma. Furthermore, physicians should keep in mind the risk of PML in MG patients with thymoma, even if their MG symptoms are in remission, and should evaluate the immunological status of the patients accordingly.\n\nAbbreviations\nADRAdriamycin\n\nCBDCACarboplatin\n\nCDDPCisplatin\n\nCMCryptococcal meningoencephalitis\n\nCPACyclophosphamide\n\nCSFCerebrospinal fluid\n\nCTChemotherapy\n\nDOXDoxorubicin\n\nDWIDiffusion-weighted images\n\nEPErythrodermic psoriasis\n\nGSGood’s syndrome\n\nHIVHuman immunodeficiency virus\n\nJCVJC virus\n\nMMonths\n\nMGMyasthenia gravis\n\nMRIMagnetic resonance imaging\n\nNRNot reported\n\nPCRPolymerase chain reaction\n\nPMLProgressive multifocal leukoencephalopathy\n\nPSLPrednisolone\n\nPTXPaclitaxel\n\nRTRadiation therapy\n\nS-1Tegafur/gimeracil/oteracil potassium\n\nSRSurgical resection of thymoma\n\nVCRVincristine\n\nVDSVindesine\n\nWWeeks\n\nYYears\n\nAcknowledgements\nWe thank Yoshiharu Miura, Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan, for advice on PML treatment, and Ann Turnley, PhD, from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.\n\nFunding\nThis work was partly supported by JSPS KAKENHI (Grant Number 17 K09768) and by a Grant-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan (Grant Number H29-Nanchitou [Nan]-Ippan-036).\n\nAvailability of data and materials\nAll data containing relevant information to support the study findings are included in the manuscript.\n\nAuthors’ contributions\nTU, NS, TK, RH, and JN collected the clinical data and interpreted the data. TU drafted the manuscript. KN and MS performed CSF real-time PCR for JCV. NS, TK, RH, JN, KN, MS, and MT helped write and revise the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe authors declare that ethics approval was not required for this case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s father for publication of this case report and any accompanying images. A copy of the written consent is available for review by the series editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Ann Neurol 2006 60 2 162 173 10.1002/ana.20933 16862584\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "18(1)", "journal": "BMC neurology", "keywords": "Good’s syndrome; Immunodeficiency; JC virus; Myasthenia gravis; Progressive multifocal leukoencephalopathy; Thymoma", "medline_ta": "BMC Neurol", "mesh_terms": "D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008875:Middle Aged; D009157:Myasthenia Gravis; D013945:Thymoma; D013953:Thymus Neoplasms", "nlm_unique_id": "100968555", "other_id": null, "pages": "37", "pmc": null, "pmid": "29631544", "pubdate": "2018-04-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26408958;23897378;1628122;889304;19054676;27497628;7919339;23568998;20298966;3024005;19695918;7073259;23857613;10360779;16862584;28245526;23509314;7800006;20149753;12499426;9160675;20561807;1698484", "title": "Progressive multifocal leukoencephalopathy associated with thymoma 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW.. 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"drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "39.5", "reaction": [ { "reactionmeddrapt": "Good syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Secondary immunodeficiency", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, SATO N, KON T, HAGA R, NUNOMURA J, NAKAMICHI K ET AL.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. BMC NEUROLOGY. 2018?18 (37):1-8", "literaturereference_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180515", "receivedate": "20180515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14898680, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "JP-IMPAX LABORATORIES, INC-2018-IPXL-01358", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN (IMMUNOGLOBULIN HUMAN NORMAL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "THYMOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MEFLOQUINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "275 MG, 1 /WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "275", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEFLOQUINE" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "40", "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Vascular access site infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, SATO N, KON T, HAGA R, NUNOMURA J, NAKAMICHI K ET AL.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. BMC NEUROLOGY. 2018?18(37):1-8", "literaturereference_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180427", "receivedate": "20180427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14821165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "JP-PFIZER INC-2018167792", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 UNK(TAPERED) ON DAY 44", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, UNK (HER LAST CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "THYMOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "39.5", "reaction": [ { "reactionmeddrapt": "Immunodeficiency", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO, T.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. BMC NEUROLOGY. 2018?18 (1):10.1186/S12883-018-1041-4", "literaturereference_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180608", "receivedate": "20180427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14821935, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "OBJECTIVE\nPatients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end-of-life care for patients with RRMM after TCE.\n\n\nMETHODS\nThe ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations.\n\n\nRESULTS\nThe survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE.\n\n\nCONCLUSIONS\nFindings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden.", "affiliations": "Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland. Electronic address: sujith.dhanasiri@bms.com.;Genesis Research, Newcastle, United Kingdom.;Genesis Research, Newcastle, United Kingdom.;Bristol Myers Squibb, Princeton, New Jersey, USA.;NYU Langone Health, New York, New York, USA.;Clinica Universidad de Navarra, Navarra, Spain.", "authors": "Dhanasiri\|Sujith\|S\|;Hollier-Hann\|Georgia\|G\|;Stothard\|Catherine\|C\|;Dhanda\|Devender S\|DS\|;Davies\|Faith E\|FE\|;Rodriguez-Otero\|Paula\|P\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clinthera.2021.09.013", "fulltext": null, "fulltext_license": null, "issn_linking": "0149-2918", "issue": null, "journal": "Clinical therapeutics", "keywords": "cross-sectional survey; health care resource use; multiple myeloma; treatment pattern; triple-class exposed", "medline_ta": "Clin Ther", "mesh_terms": null, "nlm_unique_id": "7706726", "other_id": null, "pages": null, "pmc": null, "pmid": "34736769", "pubdate": "2021-11-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Treatment Patterns and Outcomes in Triple-Class Exposed Patients With Relapsed and Refractory Multiple Myeloma: Findings From the Multinational ITEMISE Study.", "title_normalized": "treatment patterns and outcomes in triple class exposed patients with relapsed and refractory multiple myeloma findings from the multinational itemise study" }	[ { "companynumb": "CH-AMGEN-CHESP2021176306", "fulfillexpeditecriteria": "2", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "202714", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown formulation", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POMALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ELOTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOTUZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IXAZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IXAZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospitalisation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospice care", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Dhanasirl, S. Treatment Patterns and Outcomes in Triple-Class Exposed Patients With Relapsed and Refractory Multiple Myeloma: Findings From the Multinational ITEMISE Study. Clinical Therapeutics. 2021", "literaturereference_normalized": "treatment patterns and outcomes in triple class exposed patients with relapsed and refractory multiple myeloma findings from the multinational itemise study", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20211116", "receivedate": "20211116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20072813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "A case is reported of acute psychosis, including florid visual and tactile hallucinations, in an 18-year-old male after intravenous misuse of 60 mg of pseudoephedrine hydrochloride. The literature is reviewed for other cases of psychosis following pseudoephedrine use.", "affiliations": "St Cadoc's Hospital, Caerleon, Gwent NP61XQ, UK.", "authors": "Sullivan\|G\|G\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/026988119601000413", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-8811", "issue": "10(4)", "journal": "Journal of psychopharmacology (Oxford, England)", "keywords": null, "medline_ta": "J Psychopharmacol", "mesh_terms": null, "nlm_unique_id": "8907828", "other_id": null, "pages": "324-5", "pmc": null, "pmid": "22302983", "pubdate": "1996-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Acute psychosis following intravenous abuse of pseudoephedrine: a case report.", "title_normalized": "acute psychosis following intravenous abuse of pseudoephedrine a case report" }	[ { "companynumb": "GB-JNJFOC-199704-0086", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PSEUDOEPHEDRINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "999999", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PSEUDOEPHEDRINE HYDROCHLORIDE." } ], "patientagegroup": "4", "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute psychosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, tactile", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual impairment", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SULLIVAN G. ACUTE PSYCHOSIS FOLLOWING INTRAVENOUS ABUSE OF PSEUDOEPHEDRINE: A CASE REPORT. JOURNAL OF PSYCHOLOGY 01-JAN-1996?10:4:324-325. SULLIVAN G. ACUTE PSYCHOSIS FOLLOWING INTRAVENOUS ABUSE OF PSEUDOEPHEDRINE: A CASE REPORT.. JOURNAL OF PSYCHOPHARMACOLOGY 1996?10:4:(324-325).", "literaturereference_normalized": "acute psychosis following intravenous abuse of pseudoephedrine a case report", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180508", "receivedate": "20180508", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14862131, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "BACKGROUND\nRates of opioid overdose deaths are increasing in the United States, leading to intensified efforts to provide medication-assisted treatments for opioid use disorders. It is not clear what effect opioid agonist treatments (ie, the µ-opioid receptor full agonist methadone and the partial agonist buprenorphine) may have on respiratory function. However, sleep-disordered breathing has been documented in methadone maintenance pharmacotherapy, and there is emerging evidence for similar sleep-disordered breathing in buprenorphine and buprenorphine-naloxone maintenance treatment.\n\n\nOBJECTIVE\nTo provide further clinical evidence of sleep-disordered breathing emerging in the context of buprenorphine-naloxone maintenance pharmacotherapy.\n\n\nMETHODS\nThe authors report two additional cases of sleep-disordered breathing that developed in patients with severe opioid use disorders, treated successfully as outpatients with buprenorphine-naloxone maintenance. Both patients provided written consent for their clinical information to be included in this case report, and elements of their identities have been masked to provide confidentiality.\n\n\nRESULTS\nTwo adult female patients, who were stable in buprenorphine-naloxone maintenance treatment developed daytime sleepiness, were referred for evaluation and found to have sleep-disordered breathing. One patient's daytime sleepiness improved with reduction in both buprenorphine-naloxone and other sedating medications as well as initiation of a constant positive airway pressure (CPAP) device. However, the other patient could not tolerate decreases in buprenorphine-naloxone and/or CPAP initiation and her daytime sleepiness persisted.\n\n\nCONCLUSIONS\nBuprenorphine-naloxone maintenance treatment can be associated with sleep-disordered breathing. It can be difficult to differentiate the cause(s) of sleep-disordered breathing among the effects of buprenorphine-naloxone treatment itself, co-occurring conditions, such as obesity and cigarette smoking or other medications, or some combination thereof. Regardless of etiology, sleep-disordered breathing and its consequences present unique challenges to the patient in recovery from an opioid use disorder and therefore warrants careful evaluation and management.", "affiliations": "Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, University of California, San Francisco, San Francisco, California.;Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.;Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.", "authors": "DeVido\|Jeffrey\|J\|;Connery\|Hilary\|H\|;Hill\|Kevin P\|KP\|", "chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1551-7489", "issue": "11(4)", "journal": "Journal of opioid management", "keywords": null, "medline_ta": "J Opioid Manag", "mesh_terms": "D000328:Adult; D002047:Buprenorphine; D003937:Diagnosis, Differential; D019468:Disease Management; D005260:Female; D006801:Humans; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011175:Positive-Pressure Respiration; D012891:Sleep Apnea Syndromes; D013995:Time; D028761:Withholding Treatment", "nlm_unique_id": "101234523", "other_id": null, "pages": "363-6", "pmc": null, "pmid": "26312963", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "18489633;19275068;9501765;23100497;20509744;8997759;11122588;1798888;16547090;7944843", "title": "Sleep-disordered breathing in patients with opioid use disorders in long-term maintenance on buprenorphine-naloxone: A case series.", "title_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series" }	[ { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-2016-RO-00374RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE AND NALOXONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015;11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088439, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00374RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL?11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160227", "receivedate": "20160227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12123852, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-2016-RO-00373RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SUMATRIPTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUMATRIPTAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE AND NALOXONE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE AND NALOXONE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL;11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00373RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SUMATRIPTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUMATRIPTAN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "24 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "16 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL?11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160227", "receivedate": "20160227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12123851, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Myocardial injury and acute coronary syndrome have been rarely associated with amoxicillin/clavulanic acid intake. The responsible pathogenetic mechanism is described by an amplified mast cell degranulation inducing coronary artery spasm and/or acute myocardial infarction in susceptible individuals which is called Kounis syndrome. We report here a case of Kounis syndrome presented with acute coronary syndrome due to amoxicillin/clavulanic acid use. All other etiologies, including ischemic reinfarction were appropriately ruled out.", "affiliations": null, "authors": "Tavil\|Yusuf\|Y\|;Turfan\|Murat\|M\|;Türkoğlu\|Sedat\|S\|;Abaci\|Adnan\|A\|", "chemical_list": "D019980:Amoxicillin-Potassium Clavulanate Combination", "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijcard.2006.11.165", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "124(1)", "journal": "International journal of cardiology", "keywords": null, "medline_ta": "Int J Cardiol", "mesh_terms": "D054058:Acute Coronary Syndrome; D019980:Amoxicillin-Potassium Clavulanate Combination; D000787:Angina Pectoris; D017023:Coronary Angiography; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D013577:Syndrome", "nlm_unique_id": "8200291", "other_id": null, "pages": "e4-7", "pmc": null, "pmid": "17360053", "pubdate": "2008-02-20", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Kounis syndrome secondary to amoxicillin/clavulanic acid use.", "title_normalized": "kounis syndrome secondary to amoxicillin clavulanic acid use" }	[ { "companynumb": "TR-RANBAXY-2013R1-73472", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "065109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OROPHARYNGEAL PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN + CLAVULANATE" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kounis syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAVIL Y, TURFAN M, TURKOGLU S, ABACI A. KOUNIS SYNDROME SECONDARY TO AMOXICILLIN/CLAVULANIC ACID USE. INT J CARDIOL. 2008;FEB 20;124(1):E4-7", "literaturereference_normalized": "kounis syndrome secondary to amoxicillin clavulanic acid use", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150305", "receivedate": "20150305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10890252, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "Adverse reactions associated to anti-thyroid drugs include fever, rash, arthralgia, agranulocytosis and hepatitis that are thought to be hypersensitivity reactions. Five cases of pleural effusion associated to thionamides have also been reported, two with propylthiouracil and three with carbimazole.\n\n\n\nWe report here a case of a 75-year-old man admitted because of unilateral pleural effusion. The patient had a recent diagnosis of hyperthyroidism and 6 days after starting methimazole complained of pleuritic chest pain. He had elevated C-reactive protein and erythrocyte sedimentation rate and normal white blood cell count and liver enzymes. Chest radiography showed a moderate right pleural effusion and the ultrasound revealed a loculated effusion that was shown to be an eosinophilic exudate.\n\n\n\nThe temporal relationship between methimazole intake and the development of pleural effusion combined with the extensive exclusion of alternative causes, namely infectious, neoplastic and primary auto-immune diseases, led to the diagnosis of hypersensitivity reaction to methimazole. The thionamide was stopped and corticosteroid was started with complete resolution of the pleural effusion in 3 months. Awareness of this rare adverse reaction of anti-thyroid drugs is important and methimazole can be added to the list of possible etiologies of drug-induced eosinophilic pleural effusion.", "affiliations": "Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal. pgasparcosta@gmail.com.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Endocrinologia, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.", "authors": "Gaspar-da-Costa\|Pedro\|P\|;Duarte Silva\|Filipa\|F\|;Henriques\|Júlia\|J\|;do Vale\|Sónia\|S\|;Braz\|Sandra\|S\|;Meneses Santos\|João\|J\|;M M Victorino\|Rui\|R\|", "chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole", "country": "England", "delete": false, "doi": "10.1186/s40360-017-0121-1", "fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 12110.1186/s40360-017-0121-1Case ReportMethimazole associated eosinophilic pleural effusion: a case report Gaspar-da-Costa Pedro pgasparcosta@gmail.com 1Duarte Silva Filipa filipacdds@gmail.com 1Henriques Júlia juliamhenriques@gmail.com 1do Vale Sónia soniavale@net.sapo.pt 23Braz Sandra sandrabbraz@gmail.com 13Meneses Santos João joaogms@hotmail.com 13M.M. Victorino Rui rui.victorino@chln.min-saude.pt 131 0000 0001 2295 9747grid.411265.5Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035 Lisbon, Portugal 2 0000 0001 2295 9747grid.411265.5Serviço de Endocrinologia, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035 Lisbon, Portugal 3 0000 0001 2181 4263grid.9983.bFaculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal 21 3 2017 21 3 2017 2017 18 162 12 2016 28 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAdverse reactions associated to anti-thyroid drugs include fever, rash, arthralgia, agranulocytosis and hepatitis that are thought to be hypersensitivity reactions. Five cases of pleural effusion associated to thionamides have also been reported, two with propylthiouracil and three with carbimazole.\n\nCase presentation\nWe report here a case of a 75-year-old man admitted because of unilateral pleural effusion. The patient had a recent diagnosis of hyperthyroidism and 6 days after starting methimazole complained of pleuritic chest pain. He had elevated C-reactive protein and erythrocyte sedimentation rate and normal white blood cell count and liver enzymes. Chest radiography showed a moderate right pleural effusion and the ultrasound revealed a loculated effusion that was shown to be an eosinophilic exudate.\n\nConclusions\nThe temporal relationship between methimazole intake and the development of pleural effusion combined with the extensive exclusion of alternative causes, namely infectious, neoplastic and primary auto-immune diseases, led to the diagnosis of hypersensitivity reaction to methimazole. The thionamide was stopped and corticosteroid was started with complete resolution of the pleural effusion in 3 months.\n\nAwareness of this rare adverse reaction of anti-thyroid drugs is important and methimazole can be added to the list of possible etiologies of drug-induced eosinophilic pleural effusion.\n\nKeywords\nEosinophilic pleural effusionThionamidesMethimazoleHypersensitivity reactionCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nMethimazole or thiamazole, together with carbimazole and propylthiouracil, are anti-thyroid medications belonging to the class of thionamides [1]. Methimazole is the active metabolite of carbimazole and has similar pharmacological activity. Thionamides side effects are rare and include fever, rash, arthralgias, agranulocytosis and hepatitis [1]. Pleuro-pulmonary complications of these drugs are even rarer.\n\nThe mechanisms of thionamides side effects are poorly understood but are generally considered to be dose independent by immunologic hypersensitivity. Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis associated to anti-thyroid drugs have been well described [2–12]. Additionally, a drug-induced lupus-like syndrome and hypersensitivity reactions with cutaneous, renal or pulmonary involvement have also been identified [13–17]. Recently, five cases of pleural effusion induced by anti-thyroid drugs, two with propylthiouracil and three with carbimazole, have been reported in the literature [18–22].\n\nWe describe here a patient with hyperthyroidism who developed an unilateral eosinophilic pleural effusion a few days after the initiation of methimazole therapy. An extensive diagnostic evaluation excluded infectious and neoplastic diseases as well as primary auto-immune or vasculitic disease as the cause of serositis. Pleural effusion was thus considered as a manifestation of methimazole-hypersensitivity reaction. To the best of our knowledge, this is the first case of methimazole-induced pleural effusion described in the literature.\n\nCase presentation\nA 75-year-old man was admitted with unilateral right pleural effusion. He presented with pleuritic chest pain that started 4 days before and had no other relevant complaints, namely fever, diaphoresis, dyspnoea, cough, haemoptysis, rash or arthralgia.\n\nHe had a past medical history of arterial hypertension, atrial fibrillation, end-stage renal disease on haemodialysis, peripheral artery disease and prostatic hyperplasia. His ambulatory prescription consisted of enalapril, carvedilol, nifedipine, aspirin, warfarin, omeprazole and tansulosin, for more than 3 years. Amiodarone had been suspended, 2 months before, due to ocular toxicity. There was no evidence of thoracic trauma or previous asbestos exposure.\n\nTen days before hospital admission the patient had an episode of unstable angina. He underwent coronary angiography which showed a lesion in the circumflex artery and angioplasty and implantation of an intracoronary stent coated drug were performed. He started treatment with clopidogrel. By this time blood tests showed low TSH (0.055 uU/mL; reference range: 0.55–4.78 uU/mL) and high FT4 (1.81 ng/dL; reference range: 0.80–1.76 ng/dL) and FT3 (4.84 pg/mL; reference range: 2.3–4.2 pg/mL). Methimazole was started. There was no evidence of pleural effusion at that time.\n\nAt hospital admission the patient was afebrile, with a respiratory rate of 18 cycles per minute and oxygen saturation of 95% on room air. His blood pressure was 131/63 mmHg and heart rate was 76 beats per minute. Cardio-pulmonary examination revealed arrhythmic heart sounds, diminished breath sounds on the lower half of the right lung and dullness on percussion at that site was noted. All other findings on physical examination were unremarkable.\n\nLaboratory tests showed normal leucocytes (6 510/uL) and eosinophils (320/uL) counts, elevated C-reactive protein (10.9 mg/dL) and erythrocyte sedimentation rate (58 mm) and normal liver enzymes; TSH (0.019 uU/mL) was low and FT4 (2.51 ng/dL) and FT3 (7.22 pg/mL) were high; INR (1.13) was not in therapeutic range. Arterial blood gases, while the patient was in room air and after haemodialysis, showed hypoxemia (PO2: 57.6 mmHg) and metabolic alkalosis (pH: 7.48, PCO2: 37.8 mmHg, HCO3\n−: 28.9 mmol/L). Electrocardiogram revealed atrial fibrillation rhythm without acute ischaemic changes. Chest radiography showed a homogenous opacity in the lower half of the right pulmonary field and chest ultrasound findings were suggestive of pleural effusion with septa. Right-sided diagnostic thoracentesis was performed. The aspirated pleural fluid had 2277 cells/uL with 70% being macrophages, 18% eosinophils and 12% neutrophils. The effusion protein/serum protein ratio was 0.7 and the effusion lactate dehydrogenase (LDH)/serum LDH ratio was 1.8. Pleural fluid cultures revealed no bacteria or mycobacteria and no malignant cells were detected on cytological examination of pleural fluid. Bronchofibroscopy did not reveal any macroscopic lesion. Bronchoalveolar fluid cultures were negative and the cytological analysis of the fluid showed no malignant cells. Pleural biopsy was not performed due to high bleeding risk as the patient was on double anti-platelet and anticoagulation therapy. The blood cultures yielded no bacteria or mycobacteria and blood interferon gamma release assay for Mycobacterium tuberculosis was negative. Anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA) antibodies and ANCA were negative.\n\nThoracic, abdominal and pelvic computed tomography (CT) was performed and confirmed the moderate right pleural effusion with no other positive findings. Thoracic CT angiography excluded pulmonary embolism. Although Dressler syndrome was considered [23], it usually occurs after myocardial infarction rather than unstable angina and moreover, the short interval between the cardiac event and the pleural effusion did not support this hypothesis [24].\n\nTiters of thyroglobulin (Tg), anti-Tg, anti-thyroperoxidase and anti-TSH receptor antibodies were normal. The cervical ultrasonography revealed thyroid micronodules and there was no radioisotope uptake in the 99mTechnetium thyroid scintigraphy. Hyperthyroidism was interpreted as type II amiodarone induced thyrotoxicosis.\n\nAfter the exclusion of neoplastic, infectious and primary auto-immune diseases, considering an exudative pleural effusion with significant eosinophilia and a well-established temporal relation with the initiation of methimazole treatment, a diagnosis of methimazole-induced pleural effusion was made. A single organ drug hypersensitivity reaction was assumed in the absence of evidence of other organ involvement. Anti-thyroid medication was suspended, systemic corticosteroid was initiated and all other medications were maintained. Progressive and rapid clinical and laboratorial improvement was evident with normalization of inflammatory biomarkers and thyroid function and resolution of hypoxemia. Three months after methimazole was suspended there was complete resolution of pleural effusion.\n\nDiscussion\nThionamides-induced auto-immune phenomena, including pleuro-pulmonary complications, exhibit usually the features of ANCA-positive systemic vasculitis. Stankus et al. published, in 1992, the first case of propylthiouracil-induced hypersensitivity vasculitis and since then 61 cases of vasculitis associated to anti-thyroid drugs have been reported, most involving propylthiouracil [15, 25]. There are only nine reported cases of carbimazole-induced vasculitis and seven cases of vasculitis associated to methimazole [2–9, 13, 14, 17, 25–29]. In addition, a lupus-like syndrome can be induced by any of the thionamides [8, 13, 14, 21, 30]. Clinical manifestations are similar to systemic lupus erythematosus (SLE) and usually patients have positive anti-nuclear, anti-dsDNA and anti-histone antibodies [21].\n\nPleuro-pulmonary complications of thionamides are very rare and include alveolar hemorrhage, interstitial pneumonia, pulmonary cavitations and pleural effusion that are considered adverse auto-immune reactions triggered by these drugs [6, 7, 9, 18–22, 31, 32]. Five cases of anti-thyroid drug-induced pleural effusion, two with propylthiouracil and three with carbimazole, have been described in the literature [18–22]. The case reported here represents the first case of methimazole-associated pleural effusion. The temporal relationship between initiation of the drug and the appearance of pleural effusion, the resolution of the effusion after withdrawal of methimazole with administration of corticosteroid, in the absence of other potential cause for pleuritis, is consistent with the diagnosis of drug-induced pleural effusion. Our case differs from the previous reports by the short time between the initiation of the thionamide and the onset of pleural effusion that was only 6 days.\n\nPleural fluid of the two patients with propylthiouracil associated pleuritis was an eosinophilic exsudate, as in the case reported here [18, 19]. Pleural biopsy was made in one of these patients and showed chronic inflammation of the pleura with prominent eosinophils and both patients had negative auto-immune markers. None of the three patients with carbimazole-induced pleuritis had an eosinophilic exudate [20–22]. Two of these three reported cases had pleural nonspecific inflammatory infiltrates and negative auto-immunity, namely ANA and ANCA. The third patient had positive ANA, anti-dsDNA and anti-histone antibodies and pleuritis was considered as a drug-induced SLE-like syndrome.\n\nAs stated before, the mechanisms involved in these cases are most likely non-dose dependent, exactly like in drug induced liver injury where lesions occur via immunologic hypersensitivity [33] by generation of toxic metabolites [34] or alternatively metabolites that induce an immunological reaction [34, 35]. The inflammatory response with abundant eosinophils in the case reported here suggests that this represents a T cell drug hypersensitivity reaction with polarization to T helper 2 cells producing interleukin 4 and interleukin 5 that are known to induce eosinophil differentiation. Interestingly, a recent report by Uematsu et al. [36], identified a T helper 2 biased lymphocyte response in a model of methimazole acute liver injury mediated by microRNAs [36]. Another area of increasing interest is that of risk factors for methimazole adverse reactions. Thus, HLA-B*27:05 and other single nucleotide polymorphisms were identified as possible risk factors for anti-thyroid agranulocytosis [37], and the prospect that certain microRNAs with effects on lung development might represent prognostic tools in thyroid-dependent lung disease [38] has also been recently discussed.\n\nThe clinical and radiological evolution of this case was identical to the cases of pleural effusion induced by other thionamides. The anti-thyroid drug considered to be associated to the effusion was withdrawn in all patients and alternative anti-thyroid therapy options were initiated in three of the five patients [19, 20, 22]. The cessation of the drug was followed by resolution of the effusion within 3 to 5 months. Two of the five patients were given corticoesteroid for a short period of time and in decreasing dosages and in these cases a more rapid resolution of serositis was observed [19, 21]. In the present case, a diagnosis of type II hyperthyroidism, due to cytotoxic effect of amiodarone on thyroid cells, was made and thus maintenance of thionamides treatment was not required.\n\nConclusions\nIn conclusion, we describe here the first case of eosinophilic pleuritis associated to methimazole due to an hypersensitivity immune drug reaction with full remission after withdrawal the drug. Awareness of clinicians about the possibility of this drug adverse reaction may help identification of future similar cases.\n\nAbbreviations\nANAAnti-nuclear antibodies\n\nANCAAntineutrophil cytoplasmic antibody\n\nAnti-dsDNAAnti-double stranded DNA antibodies\n\nCTComputed tomography\n\nSLESystemic lupus erythematosus\n\nTgThyroglobulin\n\nAcknowledgements\nThe authors would like to thank the patient for granting consent for publication.\n\nFunding\nThis report received no research funding.\n\nAvailability of data and materials\nThe data that support the findings of this case are included in this published article.\n\nAuthors’ contributions\nPGC, JH, SV, SB and JMS analyzed and interpreted the present case and were involved in the diagnostic approach; PGC, FDS, JH, SV, SB, JMS and RMMV did a review of the literature; PGC, FDS and SB wrote a first draft. PGC, SB, SV, JMS and RMMV finalized the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor of this journal.\n\nEthics approval and consent to participate\nNot applicabale.\n==== Refs\nReferences\n1. Cooper DS Antithyroid drugs N Engl J Med 2005 352 905 17 10.1056/NEJMra042972 15745981 \n2. D’Cruz D Chesser AM Lightowler C Comer M Hurst MJ Baker LR Raine AE Antineutrophil cytoplasmic antibody-positive glomerulonephritis associated with anti-thyroid drug treatment Br J Rheumatol 1995 34 1090 1 10.1093/rheumatology/34.11.1090 8542214 \n3. Hori Y Arizono K Hara S Kawai R Hara M Yamada A Antineutrophil cytoplasmic antibodies-positive crescentic glomerulonephritis associated with thiamazole therapy Nephron 1996 74 734 5 10.1159/000189486 8956314 \n4. 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Hallberg P Eriksson N Ibañez L Bondon-Guitton E Kreutz R Carvajal A Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population Lancet Diabetes Endocrinol 2016 4 6 507 16 10.1016/S2213-8587(16)00113-3 27157822 \n38. Bjørnstad S Samara A Erichsen A Paulsen RE Glover JC Roald B Hampered lung maturation in methimazole-induced hypothyroidism in fetal chicken: morphological and molecular correlates to human fetal development Neonatology 2016 110 2 83 92 10.1159/000444656 27070722\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-6511", "issue": "18(1)", "journal": "BMC pharmacology & toxicology", "keywords": "Case report; Eosinophilic pleural effusion; Hypersensitivity reaction; Methimazole; Thionamides", "medline_ta": "BMC Pharmacol Toxicol", "mesh_terms": "D000368:Aged; D013956:Antithyroid Agents; D004804:Eosinophils; D006801:Humans; D008297:Male; D008713:Methimazole; D010996:Pleural Effusion", "nlm_unique_id": "101590449", "other_id": null, "pages": "16", "pmc": null, "pmid": "28320470", "pubdate": "2017-03-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": 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METHIMAZOLE ASSOCIATED EOSINOPHILIC PLEURAL EFFUSION: A CASE REPORT. 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ocular toxicity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GASPAR-DA-COSTA, P.. METHIMAZOLE ASSOCIATED EOSINOPHILIC PLEURAL EFFUSION: A CASE REPORT.. 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{ "abstract": "Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis.\n\n\n\nThirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured.\n\n\n\nADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AUmin: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AUmin: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study.\n\n\n\nClopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc.\n\n\n\nISRCTN63206606 . Registered 02/Dec/2014.", "affiliations": "Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece. kosdelis@gmail.com.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.", "authors": "Ntelis\|Konstantinos\|K\|;Gkizas\|Vasileios\|V\|;Filippopoulou\|Alexandra\|A\|;Davlouros\|Periclis\|P\|;Alexopoulos\|Dimitrios\|D\|;Andonopoulos\|Andrew P\|AP\|;Daoussis\|Dimitrios\|D\|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D019010:Vascular Cell Adhesion Molecule-1; D012701:Serotonin; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine", "country": "England", "delete": false, "doi": "10.1186/s12891-016-1072-1", "fulltext": "\n==== Front\nBMC Musculoskelet DisordBMC Musculoskelet DisordBMC Musculoskeletal Disorders1471-2474BioMed Central London 107210.1186/s12891-016-1072-1Research ArticleClopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study Ntelis Konstantinos +30-2610-999 693+30-2610-993 982kosdelis@gmail.com Gkizas Vasileios Filippopoulou Alexandra Davlouros Periclis Alexopoulos Dimitrios Andonopoulos Andrew P. Daoussis Dimitrios Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece 17 5 2016 17 5 2016 2016 17 21311 12 2015 11 5 2016 © Ntelis et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nActivated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis.\n\nMethods\nThirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured.\n\nResults\nADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AUmin: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AUmin: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study.\n\nConclusion\nClopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc.\n\nClinical trial registration\nISRCTN63206606. Registered 02/Dec/2014.\n\nKeywords\nSystemic sclerosisSclerodermaClopidogrelDigital ulcersPlateletshttp://dx.doi.org/http://dx.doi.org/10.13039/501100003486Hellenic Rheumatology Society and Professional Organization for Rheumatologistsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSystemic Sclerosis (SSc) is a systemic rheumatic disease characterized by obliterative vasculopathy, autoimmunity and progressive fibrosis leading to tissue injury. The skin and several internal organs are involved during the disease course; involvement of vital organs leads to increased mortality and morbidity. To date, no approved disease-modifying therapies exist for the treatment of patients with SSc. Numerous experimental drugs or interventions have been investigated for the treatment of visceral fibrosis in systemic sclerosis, some of them demonstrating promising results [1–4]. However, the need for new therapeutic targets in SSc remains crucial.\n\nThe main pathogenetic model of SSc recognizes endothelial cell injury, immune activation and fibrosis as the key points in the disease process [5, 6]. Lately, accumulating evidence suggests that platelets are not just cell fragments regulating hemostasis, but may be active players in the pathogenesis of several inflammatory or autoimmune diseases, including SSc [7–9]. Evidence suggests that there may be increased platelet activity in patients with SSc, due to the underlying vascular damage [10, 11] and many platelet-derived molecules, such as beta-thromboglobulin, thromboxane B2 and platelet factor 4, have been reported to be elevated in patients with SSc [12, 13]. A recent study has provided evidence that serotonin (5-hydroxytryptamine [5-HT]) released in peripheral tissues upon activation of platelets may induce skin fibrosis through activation of fibroblasts via 5-HT2B receptors [14]. These data point to the direction of a novel pathogenetic model of SSc where platelets and serotonin act as the link between endothelial dysfunction and fibrosis (endothelial dysfunction → platelet activation → serotonin release → fibroblast activation → fibrosis). Moreover, inhibition of platelet activity by clopidogrel treatment leads to a reduction of fibrosis in bleomycin-induced and tight skin murine models of scleroderma [14]. It is not known whether serotonin levels are increased in patients with SSc, but it has been found to be elevated in closely related conditions, such as Raynaud’s phenomenon and pulmonary hypertension [15, 16]. Antiplatelet agents, such as aspirin, which have been used previously in patients with SSc in order to improve vasculopathy have failed to show any efficacy [17]. So far, the effect of platelets inhibition by clopidogrel, a P2Y12 receptor antagonist, has not been investigated in vivo in patients with SSc. Clopidogrel is indicated for adult patients suffering from myocardial infarction or acute coronary syndrome, ischemic stroke or established peripheral arterial disease. Clopidogrel inhibits adenosine diphosphate (ADP) binding to its platelet P2Y12 receptor and subsequently the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. ADP-dependent platelet activation is one of the pathways which lead to platelet activation.\n\nIn this study we aimed to assess whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can a) effectively suppress ADP-dependent activation of platelets, b) reduce circulating levels of serotonin, a significant profibrotic mediator and finally c) favorably affect fibrosis or vasculopathy in patients with systemic sclerosis. We report herein that clopidogrel effectively inhibits ADP-dependent activation of platelets but does not improve either fibrosis or endothelial function in patients with SSc. To the contrary, it may associate with a deterioration of disease course, triggering the development of new digital ulcers.\n\nMethods\nPatients\nWe enrolled 14 patients with a diagnosis of SSc, fulfilling the 2013 ACR/EULAR criteria for the classification of the disease [18]. One patient did not comply with treatment and was withdrawn from the study. Baseline demographic and clinical characteristics of the remaining 13 patients are presented in Table 1. Most patients were female (n = 12) with a mean age of 59.5 years and had limited disease (n = 8) with a mean disease duration of 10.9 years. All patients underwent a complete physical examination and a detailed review of their medical files prior to study enrolment. Other variables were also evaluated (full blood count, biochemistry profile, autoantibody profiles, electrocardiogram and cardiac ultrasound). All patients were Anti-Scl-70 (anti-topoisomerase I antibodies) or anti-ACA (anti-centromere antibodies) positive (n = 5 and n = 8 respectively) and had no change in medications administered during the last 6 months before enrollment. None of the study subjects was under any kind of antiplatelet treatment. No change in immunosuppressive treatment was allowed during the study. Exclusion criteria included a history of gastrointestinal or cerebral bleeding. ADP-dependent platelet activation was also measured in 28 patients with RA and 22 healthy subjects for control purposes. Most patients with RA were female (75 %) with a mean age of 59 years and a mean DAS28 of 2.9; no patient was receiving any antiplatelet agent. The majority of the patients with RA were on treatment only with synthetic DMARDs (71.4 %), mainly methotrexate, while the rest of them were receiving also a biologic DMARD (28.6 %). No patient was receiving drugs, such as antidepressants (including selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors and tricyclic anti-depressants), any kind of anti-psycotic agent, anti-migraine agents (triptans), anti-convulsants, anti-parkinsonian agents, opioids and tramadol, that interfere with levels of serotonin. Healthy subjects were mostly female (90.9 %) with a mean age of 55 years and were not on any kind of antiplatelet or other treatment. APA and DD formed the Safety Board of the study and were responsible for evaluating all adverse events.Table 1 Demographics, clinical characteristics and medications of study subjects\n\nPatient no/sex/age in years\tDisease Duration in years\tType of Disease\tOrgan Involvement\tConcurrent medications\t\n1/F/47\t5\tlimited\tGI\t-\t\n2/F/62\t12\tdiffuse\tLung,PAH,GI\tCYC\t\n3/M/55\t2\tlimited\tLung,GI\t-\t\n4/F/53\t12\tdiffuse\tLung,DU,GI\tMMF, Bos\t\n5/F/53\t12\tlimited\tLung,DU,GI\tPred, RTX, Bos\t\n6/F/78\t4\tdiffuse\tLung,DU,PAH,Musc\tPred, Bos, RTX\t\n7/F/57\t21\tlimited\tLung,DU,GI\tPred, Bos\t\n8/F/58\t3\tdiffuse\tLung,GI\tRTX\t\n9/F/66\t9\tlimited\tLung,GI\tMMF\t\n10/F/59\t17\tlimited\tMusc\t–\t\n11/F/65\t8\tlimited\tLung,GI\tRTX\t\n12/F/40\t22\tdiffuse\tLung,GI,Musc\tRTX\t\n13/F/81\t15\tlimited\tGI\t–\t\nPred: low dose prednisone; Bos: bosentan; MMF: mycophenolate mofetil; CYC: cyclophosphamide; RTX: rituximab\n\nDU: digital ulcers; Musc: musculoskeletal involvement; GI: gastrointestinal involvement; PAH: pulmonary arterial hypertension\n\n\n\nTreatment\nPatients with SSc were treated with the recommended dose of clopidogrel in everyday clinical practice (75 mg). Duration of the study had been planned to be 2 years. Finally, due to early discontinuation of the study, 12 patients completed 1 year of treatment, while one patient (#13) was treated with the study drug for 10 months.\n\nIndices of internal organ function\nStandard PFTs (pulmonary function tests) were performed every 6 months during the study, including assessment of forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLco) corrected for hemoglobin concentration. PFT parameters are expressed as a percentage of normal predicted values. Estimated glomerular filtration rate (eGFR) was calculated at baseline and at 1 year with the 4 variables MDRD (Modification of Diet in Renal Disease Study Group) formula [19]. Complete cardiac ultrasound study was performed at baseline and at 12 months and right ventricular systolic pressure (RVSP) was determined.\n\nOverall functional impairment\nAssessment of functional status was performed at baseline, 6 and 12 months using the modified for Scleroderma Health Assessment Questionnaire (SHAQ) [20].\n\nClinical assessment of skin thickening\nThe modified Rodnan skin score (MRSS) [21, 22] was used for clinical assessment of skin thickening at baseline and at 1 year, by two experienced assessors (DD and KN).\n\nLevels of circulating serotonin and s-VCAM1\nWhole blood was obtained from all participants at baseline and following 14 days of treatment. Platelet poor plasma was isolated from citrate tubes following a double centrifugation at 2000 g. Following the first centrifugation the top 75 % of plasma was removed with a plastic pipette, avoiding contamination, and underwent a second centrifugation at 2000 g. After the second centrifugation, the upper 75 % purified from the sedimented platelets, formed the platelet poor plasma. Samples from strenuous punctures were excluded. Serotonin was measured in these specimens with Radioimmunoassay (RIA) technique (DIAsource ImmunoAssays). Serum was also isolated at the same time points in order to evaluate the effect of treatment on the circulating levels of soluble vascular cell adhesion protein 1 (s-VCAM1), a marker of endothelial dysfunction [23]. Enzyme-linked immunosorbent assay (ELISA) technique was employed, using commercially available kit, according to the manufacturer’s instructions (R&D Systems, Minneapolis MN, USA). All samples were stored at -70 ° C.\n\nAssessment of ADP-dependent activation of platelets\nThe effect of treatment upon platelet activity was assessed through ADP-induced aggregation of platelets, measured by Multiplate Analyser (Roche), an instrument with five channels for parallel aggregometry measurements. Platelet activation was measured at baseline, following 14 days and 1 year of treatment. After 1:2 dilution of whole blood with 0.9 % NaCl solution and incubating for 3 min in the test cuvettes at 37 °C, the agonist (ADP) was added. Platelet aggregation was continuously recorded for 6 min. The adhesion and aggregation of platelets was measured by the change of electrical resistance between two sensor wires. Impedance is transformed to arbitrary aggregation units (AU) that are plotted against time (AUmin) [24]. Resistance to clopidogrel inhibition was defined as a AUmin value ≥468 on treatment [25].\n\nStatistical analysis\nStatistical analysis was performed using the GraphPad Prism software version 5. All variables were tested for normality using D'Agostino's test. Data are presented as mean ± SEM, median or percentages, as appropriate. The paired Student’s t-test and Wilcoxon matched pairs test, were used as indicated, for normal and non-normal distributions respectively. One-way ANOVA was used for group comparisons. Unpaired t-test was used to compare unpaired values. Correlations between ADP-dependent platelet activation and other variables were analyzed by Pearson or Spearman test, as appropriate. Values of p < 0.05 were considered as statistically significant.\n\nResults\nNo evidence of increased ADP-dependent platelet activation in patients with SSc\nWe first evaluated the ADP-dependent activation of platelets in patients with SSc compared to patients with RA and healthy subjects. No statistically significant differences were found between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AUmin: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). These data are diagrammatically depicted in Fig. 1a.Fig. 1 ADP-dependent platelet activation in patients with SSc is not increased compared to patients with RA and healthy subjects (a). Clopidogrel effectively inhibits ADP-dependent platelet activation in patients with SSc (b)\n\n\n\nSince many patients in our cohort had long standing disease we next sought to explore whether ADP-dependent platelet activation in patients with SSc correlates with disease duration. We found that ADP-dependent platelet activation in patients with early disease (as defined by disease duration ≤ 4 years, n = 3) was similar to that of patients with long standing disease (mean ± SEM AUmin: 315.7 ± 105.4 vs 415.0 ± 70.1 in patients with early vs late disease, respectively, p = 0.49). Moreover, no significant association of ADP-dependent platelet activation with age, gender, PFTs or MRSS in patients with SSc was found.\n\nThese data indicate that ADP-dependent platelet activation is not increased in patients with SSc, even in those with early disease despite the underlying vasculopathy; therefore, this particular pathway of platelet activation does not seem to be crucially involved in SSc pathogenesis.\n\nClopidogrel treatment effectively inhibits ADP-dependent activation of platelets in patients with SSc\nWe next assessed the effect of clopidogrel on ADP-dependent activation of platelets in patients with SSc. Following 14 days of clopidogrel treatment a significant reduction of ADP-depended activation of platelets was found in patients with SSc (mean ± SEM AUmin: 392.1 ± 58.4 vs 163.8 ± 51.7, prior to and following treatment respectively, p = 0.014). These data are shown in Fig. 1b. This effect was sustained following one year of treatment (mean ± SEM AUmin: 157.2 ± 39, p = 0.005 compared to baseline). Two patients (15.4 %) showed resistance to clopidogrel inhibition and displayed high platelet reactivity (497 and 594 AU*min) despite treatment. These data show that clopidogrel is an effective inhibitor o ADP-dependent platelet activation in patients with SSc since the percentage of patients displaying resistance to clopidogrel inhibition (15.4 %) is even lower than that reported for the general population which is estimated to be up to 30 % [26, 27].\n\nClopidogrel treatment does not affect serotonin levels\nWe next assessed whether effective suppression of ADP-dependent platelet activation by clopidogrel can decrease circulating serotonin levels, a significant profibrotic mediator. Serotonin levels in platelet poor plasma did not change following 14 days of treatment with clopidogrel (mean ± SEM ng/dl: 178.3 ± 17.4 vs 210.6 ± 28.6, prior to and following treatment respectively, p = 0.17), despite the effective suppression of ADP-dependent activation of platelets at the same time point. Data are shown in Fig. 2a.Fig. 2 Effect of clopidogrel on serotonin and sVCAM1 levels. No change in serotonin levels in platelets poor plasma was found in patients with SSc following 14 days of treatment with clopidogrel (a). sVCAM1 levels are significantly increased following clopidogrel treatment in patients with SSc (b)\n\n\n\nClopidogrel treatment associates with worsening of endothelial function\nWe further evaluated the results of clopidogrel treatment on soluble VCAM1 levels as a marker of endothelial dysfunction/injury. There was a statistically significant increase of s-VCAM1 levels following 14 days of clopidogrel treatment (optical density mean ± SEM: 2.339 ± 0.211 vs 2.651 ± 0.139 before and following treatment respectively, p = 0.03) as shown in Fig. 2b. These data indicate that clopidogrel treatment does not improve but may actually worsen endothelial function in patients with SSc.\n\nClopidogrel treatment may associate with the development of new digital ulcers in patients with SSc\nThree patients, all with limited disease, developed new digital ulcers during the study; 2 of them did not have a history of digital ulcers. Patient #3 had early disease with a 3 year history of Raynaud’s phenomenon before the diagnosis, but no history of ulcers. Most striking, patient #13 had a longstanding disease of 15 years; she never had digital ulcers. Patient #4 had a 12 year history of disease but she has not developed any ulcers for the last 8 years, while on bosentan treatment. Patients #3, #4 and #13 developed the ulcers following 10, 9 and 10 months of treatment, respectively. In patients #13 and #3 we initiated treatment with bosentan with a good response after a short period, while patient #4 was treated with iloprost and antibiotics showing also a rapid improvement. None of the patients had any changes in everyday lifestyle during the study including exposure to cold. Following the development of digital ulcers in patient #13 the Safety Board of the study decided to withdraw all patients from the study medication, concluding that there may be an association between treatment and development of new ulcers. At that time point all patients, apart from patient #13, had completed 1 year on treatment. No other serious adverse events were recorded during the study. The main side effects included a transient rash after treatment initiation in patient #7 and minor bruising episodes in patients #5 and #9.\n\nEffect of Clopidogrel treatment on clinical outcomes\nTo evaluate any potential clinical effect of clopidogrel treatment we performed a complete physical exam, evaluation of skin thickening, evaluation of pulmonary function, basic laboratory work up and finally evaluation of general functional status. Clopidogrel treatment had no significant effect on skin thickening (mean ± SEM 10.69 ± 0.62 vs 9.85 ± 0.84 at baseline vs 1 year, respectively, p = 0.12). We did not detect any statistically significant differences in all indices of internal organ function we examined. FVC remained stable following 1 year of treatment (mean ± SEM 93.75 ± 5.58 vs 92.67 ± 5.04 at baseline vs 1 year, respectively, p = 0.69), the same was found for DLco (mean ± SEM 65.08 ± 4.31 vs 62.67 ± 4.85 at baseline vs 1 year respectively, p = 0.39). SHAQ also showed no significant change following one year of treatment with clopidogrel (mean ± SEM: 0.80 ± 0.11 vs 0.98 ± 0.14, p = 0.16). RVSP and EGFR also remained stable following 1 year of treatment. Data are diagrammatically shown in Fig. 3.Fig. 3 Effects of clopidogrel on clinical outcomes. Clopidogrel treatment does not have any significant impact on clinical outcomes (MRSS (a), FVC (b), DLco (c) and EGFR (d)) in patients with SSc\n\n\n\nDiscussion\nWe report herein the results of an open label, proof of principle study evaluating the efficacy of clopidogrel in patients with SSc. So far, ADP-dependent platelet activation has not been investigated in SSc with newer techniques. The potential role of platelets in the pathogenesis of SSc has been explored in SSc but data are still controversial. Several studies demonstrate increased platelet activation using different agents as agonists [28, 29], but this was not a consisted finding [30].\n\nIn our study we found no evidence of increased ADP-dependent platelet activation in patients with SSc, even in those with early disease, compared to patients with RA and healthy subjects, indicating that this particular pathway of platelet activation may not be crucially involved in SSc pathogenesis. However, one should take into account that SSc is an extremely heterogeneous disease and therefore, definite conclusions cannot be drawn based on data derived from a small number of patients. One cannot exclude the possibility that there may be a subset of patients with SSc displaying increased ADP dependent platelet activation; we cannot rule out that in these particular patients clopidogrel might have some efficacy.\n\nMoreover, we demonstrated that clopidogrel can effectively inhibit the ADP-dependent activation of platelets in the majority of SSc patients. Previous studies have reported that resistance to clopidogrel inhibition in particular populations, such as patients with chronic kidney failure under hemodialysis, can reach up to 84 % [31]. In our study only two of 13 SSc patients showed resistance to clopidogrel; this percentage (15.4 %) is even lower than that reported for the general population, which is estimated to be up to 30 % [26, 27].\n\nBased on experimental data which indicate that platelets may be involved in the fibrotic process, we aimed at exploring whether platelet inhibition by clopidogrel could favorably affect fibrosis in patients with SSc, offering thus an adjunct therapeutic approach for the disease. There is evidence that serotonin is an important mediator in SSc which links vascular damage, platelets and fibrosis. Serotonin, a molecule stored in platelets, has been shown to possess profibrotic properties [32, 33]. However, there is no robust evidence that plasma free serotonin is increased in SSc. Biondi et al reported such a finding in patients with secondary Raynaud’s phenomenon [15], but Klimiuk et al found no evidence of this increase in patients with SSc [34]. In our study, effective inhibition of ADP dependent platelet activation with clopidogrel did not affect serotonin levels.\n\nFinally, our data suggest that clopidogrel may associate with worsening of endothelial function and development of new digital ulcers in patients with SSc. Although platelets are considered to promote vasoconstriction, it is also known that they produce nitric oxide (NO) as well [35]. NO is a vasodilator which mainly derives from endothelial cells and consists an important modulator of vascular tone. It has been found that NO production from platelets is increased in chronic kidney failure [36], another condition characterized by generalized vasculopathy, and may have a protective role against cardiovascular risk. In addition, there are also studies demonstrating some protective features of platelets regarding fibrosis and vascular function. In two murine models of liver damage platelets seem to prevent fibrosis [37] and promote liver tissue repair [38]. Joshi et al showed that platelet depletion delays resolution of necrosis in the postischemic liver, suggesting that the presence of platelet-derived factors is necessary for tissue remodeling [37].\n\nMoreover, Holowatz et al reported that platelet inhibition with clopidogrel attenuated reflex vasodilation, in middle aged women, suggesting platelet involvement in reflex vasodilation through the release of vasodilating factors. Investigators found that clopidogrel decreased skin blood flow responses during hyperthermia [39]. This effect may be of importance in SSc patients and may explain the development of new digital ulcers in our study. All the above data suggest that platelets under certain conditions may have properties which improve endothelial function and enhance vasodilation and tissue repair, rather than provoke tissue injury.\n\nConclusions\nOverall, our data indicate that clopidogrel may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis. This study in combination with previous reports of failure of antiplatelet agents in SSc, indicates that platelets may not play a crucial role in SSc pathophysiology, at least in late stages. Moreover, our data indicate that clopidogrel should be used cautiously in patients with SSc. This becomes even more important nowadays, as it is becoming clear that patients with SSc have increased cardiovascular morbidity and frequently need antiplatelet treatment [40]. Aspirin may be a more suitable therapeutic option for these patients. Our findings originate from a small uncontrolled trial and further investigation with larger cohorts is warranted.\n\nEthics approval and consent to participate\nA local (Patras University Hospital, Patras, Greece) Ethics Committee approved the study protocol (which fulfilled the Declaration of Helsinki requirements) and written informed consent was obtained from all participants.\n\nConsent for publication\nNot applicable.\n\nAvailability of data and materials\nExperimental data are available in LabArchives repository https://mynotebook.labarchives.com/share_attachment/kostas/MTkuNXwxNzk0NjAvMTUtMi9UcmVlTm9kZS8zODM0NTIxMjM4fDQ5LjU=xMjM4fDQ5LjU=\n\nAbbreviations\nSScSystemic Sclerosis\n\n5-HT5-hydroxytryptamine\n\nRArheumatoid arthritis\n\nADPadenosine diphosphate\n\nAnti-Scl-70anti-topoisomerase I antibodies\n\nanti-ACAanti-centromere antibodies\n\nPFTspulmonary function tests\n\nFVCforced vital capacity\n\nDLcodiffusing capacity of carbon monoxide\n\nRVSPventricular systolic pressure\n\neGFRestimated glomerular filtration rate\n\nMDRDmodification of diet in renal disease study group formula\n\nSHAQscleroderma health assessment questionnaire\n\nMRSSmodified Rodnan skin score\n\nRIAradioimmunoassay\n\ns-VCAM1soluble vascular cell adhesion protein 1\n\nELISAenzyme-linked immunosorbent assay\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nDA, APA and DD participated in the conception and design of the study. DA and APA revised the manuscript. KN and DD performed the literature search, the statistical analysis and wrote the manuscript. KN, AF and VG performed the experimental part of the study. PD helped to interpret the data. All authors read and approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis work was supported by the Hellenic Rheumatology Society and Professional Organization for Rheumatologists (a non-profitable organization which did not interfere in any stage of this study)\n==== Refs\nReferences\n1. Daoussis D Liossis S-NC Tsamandas AC Kalogeropoulou C Kazantzi A Sirinian C Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study Rheumatology (Oxford) 2010 49 2 271 80 10.1093/rheumatology/kep093 19447770 \n2. Naraghi K van Laar JM Update on stem cell transplantation for systemic sclerosis: recent trial results Curr Rheumatol Rep 2013 15 5 326 10.1007/s11926-013-0326-2 23516015 \n3. 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Gkaliagkousi E Ritter J Ferro A Platelet-derived nitric oxide signaling and regulation Circ Res 2007 101 7 654 62 10.1161/CIRCRESAHA.107.158410 17901370 \n36. Brunini TMC Yaqoob MM Novaes Malagris LE Ellory JC Mann GE Mendes Ribeiro AC Increased nitric oxide synthesis in uraemic platelets is dependent on L-arginine transport via system y(+)L Pflugers Arch 2003 445 5 547 50 10.1007/s00424-002-0978-7 12634924 \n37. Joshi N, Kopec AK, O’Brien KM, Towery KL, Cline-Fedewa H, Williams KJ, et al. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost. 2015;13(1):57–71.\n38. Nocito A Georgiev P Dahm F Jochum W Bader M Graf R Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice Hepatology 2007 45 2 369 76 10.1002/hep.21516 17256748 \n39. Holowatz LA Jennings JD Lang JA Kenney WL Systemic low-dose aspirin and clopidogrel independently attenuate reflex cutaneous vasodilation in middle-aged humans J Appl Physiol 2010 108 6 1575 81 10.1152/japplphysiol.01362.2009 20360429 \n40. Chu S-Y Chen Y-J Liu C-J Tseng W-C Lin M-W Hwang C-Y Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study Am J Med 2013 126 11 982 8 10.1016/j.amjmed.2013.06.025 24157289\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2474", "issue": "17()", "journal": "BMC musculoskeletal disorders", "keywords": "Clopidogrel; Digital ulcers; Platelets; Scleroderma; Systemic sclerosis", "medline_ta": "BMC Musculoskelet Disord", "mesh_terms": "D000244:Adenosine Diphosphate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000077144:Clopidogrel; D004730:Endothelium, Vascular; D005260:Female; D005385:Fingers; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors; D000075082:Proof of Concept Study; D058921:Purinergic P2Y Receptor Antagonists; D012595:Scleroderma, Systemic; D012701:Serotonin; D012883:Skin Ulcer; D013988:Ticlopidine; D019010:Vascular Cell Adhesion Molecule-1", "nlm_unique_id": "100968565", "other_id": null, "pages": "213", "pmc": null, "pmid": "27188755", "pubdate": "2016-05-17", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "12922968;12796140;6386002;3397197;2774700;1888199;2151867;1839040;1382417;7562759;8712862;9146760;10075613;15818719;15837243;17256748;17901370;17917538;19264241;19167402;19132559;19521548;19447770;20360429;20564397;20828644;20004954;21090968;21518801;21985070;22244622;22868927;23516015;24092682;24157289;25353084;11031209;12465153;12634924;6229551", "title": "Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study.", "title_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study" }	[ { "companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-118852", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLERODERMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKEL DIS. 2016;MAY 17:213:1-8", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13838994, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "GR-SA-2016SA108038", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020839", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": "6", "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP, ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKELET DISORD. 2016;17:213. DOI: 10.1186/S12891-016-1072-1. ACCESSED: 2016 MAY 17.", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20160614", "receivedate": "20160614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12464824, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-118851", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLERODERMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOSENTAN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKEL DIS. 2016;MAY 17:213:1-8", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13838997, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-118790", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLERODERMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKEL DIS. 2016;MAY 17:213:1-8", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13838987, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "GR-SA-2016SA108009", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020839", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOSENTAN." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP, ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKELET DISORD. 2016;17:213. DOI: 10.1186/S12891-016-1072-1. ACCESSED: 2016 MAY 17", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20160615", "receivedate": "20160615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12468798, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "GR-SA-2016SA107879", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020839", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": "5", "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin ulcer", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NTELIS K, GKIZAS V, FILIPPOPOULOU A, DAVLOUROS P, ALEXOPOULOS D, ANDONOPOULOS AP, ET AL. CLOPIDOGREL TREATMENT MAY ASSOCIATE WITH WORSENING OF ENDOTHELIAL FUNCTION AND DEVELOPMENT OF NEW DIGITAL ULCERS IN PATIENTS WITH SYSTEMIC SCLEROSIS: RESULTS FROM AN OPEN LABEL, PROOF OF CONCEPT STUDY. BMC MUSCULOSKELET DISORD. 2016;17:213. DOI: 10.1186/S12891-016-1072-1 ACCESSED: 2016 MAY 17.", "literaturereference_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20160614", "receivedate": "20160614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12464810, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "A 58-year-old woman presented with a 3-week history of a pruritic rash, which had started a week after commencing treatment with amlodipine. On physical examination, large, well-demarcated erythematous plaques, surrounded by small clusters of clear vesicles, were seen on the patient's torso. Subepidermal blisters with neutrophils and eosinophils were seen in a skin biopsy, and direct immunofluorescence showed deposition of IgA along the basement membrane, in keeping with a diagnosis of linear IgA dermatosis (LAD). Amlodipine was discontinued, and the patient was started on prednisolone 30 mg, supplemented shortly afterwards by dapsone, which resulted in prompt resolution of the rash. Only a few cases of drug-induced LAD have been reported, mostly in association with vancomycin. To our knowledge, this is the first reported case precipitated by amlodipine.", "affiliations": "Department of Dermatology, Mint Wing A, St Mary's Hospital, London, UK. lynette_low@hotmail.com", "authors": "Low\|L\|L\|;Zaheri\|S\|S\|;Wakelin\|S\|S\|", "chemical_list": "D002121:Calcium Channel Blockers; D007070:Immunoglobulin A; D017311:Amlodipine", "country": "England", "delete": false, "doi": "10.1111/j.1365-2230.2011.04297.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0307-6938", "issue": "37(6)", "journal": "Clinical and experimental dermatology", "keywords": null, "medline_ta": "Clin Exp Dermatol", "mesh_terms": "D017311:Amlodipine; D002121:Calcium Channel Blockers; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007070:Immunoglobulin A; D008875:Middle Aged; D012871:Skin Diseases", "nlm_unique_id": "7606847", "other_id": null, "pages": "649-51", "pmc": null, "pmid": "22299719", "pubdate": "2012-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Amlodipine-induced linear IgA disease.", "title_normalized": "amlodipine induced linear iga disease" }	[ { "companynumb": "GB-RANBAXY-2012R1-59998", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDROFLUMETHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDROFLUAZIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077974", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Linear IgA disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LOW L, ZAHERI S, WAKELIN S. AMLODIPINE-INDUCED LINEAR IGA DISEASE. CLIN EXP DERMATOL. 2012;AUG;37(6):649-51", "literaturereference_normalized": "amlodipine induced linear iga disease", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150120", "receivedate": "20120924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8803092, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.", "affiliations": "Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; and.;Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; and.;Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands.;Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.", "authors": "Berger\|Gerbrig\|G\|;Kroeze\|Leonie I\|LI\|;Koorenhof-Scheele\|Theresia N\|TN\|;de Graaf\|Aniek O\|AO\|;Yoshida\|Kenichi\|K\|;Ueno\|Hiroo\|H\|;Shiraishi\|Yuichi\|Y\|;Miyano\|Satoru\|S\|;van den Berg\|Eva\|E\|;Schepers\|Hein\|H\|;van der Reijden\|Bert A\|BA\|;Ogawa\|Seishi\|S\|;Vellenga\|Edo\|E\|;Jansen\|Joop H\|JH\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1182/blood-2017-09-805879", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "131(16)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000328:Adult; D000368:Aged; D064592:Autografts; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D009196:Myeloproliferative Disorders; D016609:Neoplasms, Second Primary; D012189:Retrospective Studies", "nlm_unique_id": "7603509", "other_id": null, "pages": "1846-1857", "pmc": null, "pmid": "29311096", "pubdate": "2018-04-19", "publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT.", "title_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct" }	[ { "companynumb": "NL-TEVA-2019-NL-1004151", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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"reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848767, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019072446", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DANAZOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSPLANT FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DANAZOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ERYTHROPOIETIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSPLANT FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROPOIETIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mean cell volume increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190228", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15986197, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-LANNETT COMPANY, INC.-NL-2019LAN000140", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 TIMES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 TIMES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 TIMES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 TIMES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DANAZOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077246", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSPLANT FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DANAZOL CAPSULES USP, 200 MG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERYTHROPOIETIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRANSPLANT FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROPOIETIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mean cell volume increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190215", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15968047, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-PFIZER INC-2019072503", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Berger G, Kroeze LI, Koorenhof-Scheele TN, de Graaf AO, Yoshida K et al.. Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT.. Blood. 2018;131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20220104", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17114158, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "NL-MYLANLABS-2019M1003901", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT. Blood. 2018;131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20211231", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17114578, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000042", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15981666, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000032", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood stem cell transplant failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL... EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200131", "receivedate": "20200131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17356019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NL-PFIZER INC-2019055626", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF LOPP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, 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"PROCARBAZINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF LOPP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15951269, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003892", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131 (16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15934529, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000033", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931749, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003873", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848789, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003872", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848852, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003887", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-ROCHE-2264041", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", 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"UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-57.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200622", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15975872, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000034", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOTHERAPY" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931822, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019070413", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER, G.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190220", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15976352, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003876", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848770, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019070587", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLEGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15985960, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-PFIZER INC-2019070508", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15981660, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003866", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH-DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850420, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003853", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, 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"reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190118", "receivedate": "20190118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15844670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003868", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848790, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-TEVA-2019-NL-1004150", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190131", "receivedate": "20190131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15896595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003899", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848905, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019057192", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (HIGH DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "209191", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, EDO. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190130", "receivedate": "20190130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15889731, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2020M1011892", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "200914", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200204", "receivedate": "20200204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17367321, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NL-MYLANLABS-2019M1003858", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850411, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019072516", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131:16:1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190228", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15984451, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003888", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, 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"patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mean cell volume increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003856", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190118", "receivedate": "20190118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15844683, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000038", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOTHERAPY" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931933, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019045307", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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{ "abstract": "Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA). We present a case of acute chest pain in a 58-year-old male with severe asthma, which regressed after sublingual administration of nitroglycerine. At the time of hospital admission, there were non-specific ST-changes on the ecg, coronary enzymes were increased, and the patient was concluded to have a non-ST-elevation myocardial infarction, and treated as such. A subacute cardiac catheterization showed no signs of significant coronary stenosis. During the next days, there was increasing pain and reduced strength in both feet. Paraclinical imaging and neurological examinations could not explain the symptoms, and physiotherapy was initiated. At the time, no connection to patient's diagnosis of severe asthma was made. The patient was seen in the respiratory outpatient clinic for a routine check-up, three weeks after the initial hospital admission. At this point, there was increasing pain in both legs and the patient had difficulty walking and experienced increasing dyspnea. Blood eosinophils were elevated (12.7 × 10(9)/L), and an acute HRCT scan showed bilateral peribronchial infiltrates with ground glass opacification and small noduli. A diagnosis of EGPA was established, and administration of systemic glucocorticoids was initiated. A year and a half later, there is still reduced strength and sensory loss. This case illustrates that it is important to consider alternative diagnoses in patients with atypical symptoms and a low risk profile. Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), which makes a quick diagnosis and prompt initiation of correct treatment imperative.", "affiliations": "Department of Lung medicine, Bispebjerg University Hospital, Denmark.;Department of Lung medicine, Bispebjerg University Hospital, Denmark.", "authors": "Bang\|Cæcilie Larsen\|CL\|;Porsbjerg\|Celeste Michala\|CM\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2016.08.004", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30077-610.1016/j.rmcr.2016.08.004Case ReportThink twice – Diagnostic delay in a patient with acute chest pain Bang Cæcilie Larsen bang.caecilie@gmail.com∗Porsbjerg Celeste Michala Department of Lung medicine, Bispebjerg University Hospital, Denmark∗ Corresponding author. bang.caecilie@gmail.com20 8 2016 2016 20 8 2016 19 94 97 1 5 2016 12 8 2016 15 8 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA).\n\nWe present a case of acute chest pain in a 58-year-old male with severe asthma, which regressed after sublingual administration of nitroglycerine. At the time of hospital admission, there were non-specific ST-changes on the ecg, coronary enzymes were increased, and the patient was concluded to have a non-ST-elevation myocardial infarction, and treated as such.\n\nA subacute cardiac catheterization showed no signs of significant coronary stenosis. During the next days, there was increasing pain and reduced strength in both feet. Paraclinical imaging and neurological examinations could not explain the symptoms, and physiotherapy was initiated. At the time, no connection to patient's diagnosis of severe asthma was made.\n\nThe patient was seen in the respiratory outpatient clinic for a routine check-up, three weeks after the initial hospital admission. At this point, there was increasing pain in both legs and the patient had difficulty walking and experienced increasing dyspnea. Blood eosinophils were elevated (12.7 × 109/L), and an acute HRCT scan showed bilateral peribronchial infiltrates with ground glass opacification and small noduli.\n\nA diagnosis of EGPA was established, and administration of systemic glucocorticoids was initiated. A year and a half later, there is still reduced strength and sensory loss.\n\nThis case illustrates that it is important to consider alternative diagnoses in patients with atypical symptoms and a low risk profile.\n\nHeart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), which makes a quick diagnosis and prompt initiation of correct treatment imperative.\n\nKeywords\nAsthmaAcute chest painEosinophilic granulomatosis with polyangiitisEGPA\n==== Body\n1 Introduction\nEGPA is a vasculitis of the small and medium size arteries. EGPA is associated with severe asthma and eosinophilia in blood and tissue [1]. The diagnostic criteria accordingly to the American College of Rheumatology (ACR), is the presence of four or more of these six:\n\n1) Asthma, 2) Greater than ten percent eosinophils on the differential leucocyte count, 3) Mononeuropathy (including multiplex) or polyneuropathy, 4) Migratory or transient pulmonary opacities detected radiographically, 5) paranasal sinus abnormality, 6) Biopsy containing a vessel showing accumulation of eosinophils in extravascular areas [2].\n\nThere are great variations in the clinical presentation of EGPA, with cardiac involvement within about one third of the patients [3] and the clinical presentation also varies according to ANCA status with higher frequency of cardial involvement in patients with ANCA negative status [4].\n\nHere, we will discuss the importance of considering a diagnosis of EGPA in patient with previously known asthma who develops chest pain. Specifically, the presence of symptoms from more than one organ system should lead the thought to a systemic disease such as EGPA, being rare but serious.\n\n2 Case presentation\nSudden chest pain developed in a 56-year old male, ex-smoker with 15 pack years, normal BMI, and very physically active, performing triathlon and cycling 40 km per day.\n\nThere was no previous history of heart disease, but two years earlier the patient was diagnosed with asthma, with symptoms related to exercise.\n\nThe asthma was highly unstable and difficult to treat, with over 6 asthma exacerbations per year, requiring frequent courses of oral prednisone. The anti-asthmatic treatment included high-dose inhaled corticosteroids, long-acting beta-2-agonist, long-acting anticholinergic, theophylline and montelukast.\n\nDespite a daily dose of 15 mg prednisone daily for a period, the patient continued to have many exacerbations. The exacerbations receded after omalizumab was commenced. Prior to the admission there was no worsening of the asthma symptoms.\n\nThe chest pain lasted for hours, and the patient described a difficulty of reaching his standard max pulse during exercise the days before. At admission, the respiration frequency was 13, heart rate 60, blood pressure 110/70 and the saturation was 97% without oxygen supplement. Auscultation examination was normal.\n\nThe electrocardiogram (ECG) showed sinus rhythm, heart rate of 55 and no significant signs of infarction, but there was hammock-like ST changes in the antero-lateral leads. There was a cardial troponin I elevation up to 25800 ng/L and creatine kinase MB elevation up to 96.7 μg/L, and an eosinophil count of 3.57 × 109/L, C-Reactive protein (CRP) 8.\n\nEchocardiography (ECCO) showed normal ejection fraction and a computed axial tomography scan (CT) scan of the heart was also normal.\n\nIt was suspected that the patient had a non ST-elevation myocardial infarction, and after administration of sublingual nitroglycerin, the pain regressed. Cardiac catheterization showed a non-significant stenosis, too small for intervention.\n\nThe subsequent day, the patient developed pain in the right groin, at the site where he had been catheterized. A hematoma with a diameter of 5 × 10 cm was found on ultrasound, and interpreted to be the cause of the pain. Later, in addition to the pain, the patient described decreased sensibility and strength of the right foot.\n\nUltrasound of the right groin showed edema, no sign of pseudo aneurism, and again, normal echocardiography.\n\nOn day five, the patient experienced that the left foot suddenly gave way under him. A neurologic exam showed decreased sensibility laterally on the left leg, and he was unable to walk on toes and heels. Because of the pain and decreased sensibility and strength, a CT of the abdomen and a Magnetic resonance scan (MRI) of the columna was performed. The CT scan showed no sign of retroperitoneal bleeding and the MRI scan showed slight protrusion of the discus on level L4/L5, otherwise normal. Electromyography was normal, and the assessment by the neurologist was that the symptoms was of non-organic origin (functional).\n\nThe patient was then referred for physiotherapy and he was released from the hospital on aspirin, brilique and simvastatin.\n\nOn day twenty-two, the patient came for a planned routine check-up at the outpatient clinic at the department of respiratory medicine. At this point, bilateral loss of strength was pronounced and he was mobilized on crutches, and experienced progressive sensory loss and dysesthesia in both legs, now with a stocking distribution.\n\nWhen examined, he was found to be short of breath, the temperature was 38.4° Celsius, and there was right sided peroneal paresis.\n\nHis eosinophil count was 12.7 × 109/L, antineutrophil cytoplasmatic antibodies (ANCA) was negative, the total white blood cell count was 18.8 × 109/L and CRP 48 mg/L.\n\nAn acute high resolution CT scan (HRCT, Fig. 1) of the lungs was performed, and showed peribronchial consolidated infiltrates and areas with subpleural ground glass attenuation in the right lower lobe (1d). Bilaterally there were small nodules. Compared to the previous CT scan of the heart, there was now an increased size of the heart, and pericardial effusion. ECCO showed thickening of the myocardium, pericardial effusion (5mm), and estimated ejection fraction of 40%. There was a slightly increase of troponin and creatin kinase MB. There was no sign of arrhythmia.\n\nThe patient was admitted to a tertiary lung and cardiology department, on suspicion of pericarditis or endocarditis, and immunosuppressive therapy was started immediately (see below).\n\nThe diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss) was made on the basis of the combination of cardial involvement, lung affection, and the presence of polyneuropathy, and highly elevated eosinophils, on a background of severe asthma.\n\n3 Differential diagnosis\nAt the initial admission, the chest pain which regressed after administration of nitroglycerine, and the coronary enzyme elevation, as well as the small stenosis on heart catheterization could be explained as NSTEMI. However, the stenosis was insignificant, the CT of the heart was normal and the patient developed neurological symptoms shortly after admission. The hematoma in the hours after heart catheterization could initially explain the dysesthesia, but the increase and the loss of strength in addition, and the dissemination to the left foot as well, were not likely to be caused by the hematoma. The insignificant protrusion of discs seen on the MRI could not explain the neurological symptoms, and especially combined with the cardial involvement. Since no biopsy could verify vasculitis, and no paraclinical examination could explain the symptoms, it was considered that they could be of non-organic origin. A contact to the asthma specialist who followed the patient or a MRI scan of the heart might have given the diagnosis earlier.\n\nThe frequent treatment with prednisone could have masked eventual previous neurological symptoms and maybe even chest pain.\n\nThe treatment with omalizumab could have caused the angina and the later thrombosis, as this is reported as side effects [5]. But it seems unlikely that omalizumab alone could have caused both the pericardial effusion, the high eosinophil count, and the neurological symptoms.\n\n4 Treatment\nHigh dose methylprednisone was initiated in a dose of 1 g three times a day for the first three days. On day two, 800 mg of cyclophosphamide was added. After the first three days, the prednisone dose was run down to 50 mg per day and further reduced over the next days. The treatment with immunosuppressant was maintained with orally methotrexate once a week for three months, this was then converted to intravenously administered cyclophosphamide once a month, because of persisting peroneal paresis and development of a deep venous thrombosis.\n\n5 Outcome and follow-up\nAt the end of the high dose methylprednisone, the eosinophil count had normalized and the dysesthesia had regressed. Likewise, the dyspnea disappeared. Within a few days, the TnI level normalized, EF normalized within weeks and the pericardial effusion regressed.\n\nThe following weeks, the paresis of the feet improved, but the paresis persisted in the right peroneal nerve. A year and a half later there is still peroneal paresis, but no sign of relapse of EGPA.\n\n6 Discussion\nThe patient presented here has both asthma, hypereosinophilia, polyneuropathy and migratory infiltrates in both lungs, and thereby meets four out of the six diagnostic criteria listed by the ACR (see “Introduction”). EGPA is a rare vasculitis, and develops especially among patients with asthma and eosinophilia [6]. This vasculitis has both pulmonary and extra pulmonary involvement, and there exists a great span in the clinical presentation with symptoms from the lungs and upper airways (asthma), skin, the cardiovascular system, the peripheral nervous system, the kidneys, the gastrointestinal tract and the musculoskeletal system [4], [6].\n\nCardial involvement in EGPA is serious and frequent. The most frequent described findings are pericardial effusion and clinical signs of heart failure [3]. ECG changes with ST abnormalities and arrhythmias, MRI with sign of endocarditis and cardiomyopathy, and signs of valve dysfunction and elevated troponins is also described [3]. In the referenced study, all patients with cardial involvement previously had no cardial symptoms. EGPA was associated with high eosinophil count at the time of diagnosis, as was the case presented here.\n\nCardial symptoms as the presenting symptom of EGPA are described in similar cases [7], [8], [9], with manifestations such as pericardial effusion [7], [8], [9] elevated troponins [8] and reduced left ventricular function and ECG changes with new Q-waves [9].\n\nOnly one case was similar to ours, regarding presenting symptoms of angina, with no severe risk factors of heart disease, on a background of late-onset asthma, and with concomitant development of polyneuropathy during admission. However, fever and transient visual disturbances was described prior to admission [10].\n\nOnly a minority of EGPA patients are positive for ANCA (14 and 28% [3], [4]). Two studies have suggested that ANCA status among EGPA patients is associated with different organ involvement. ANCA negative status was associated with cardial involvement, as it was the case with the patient presented here. ANCA positive status was more frequent among patients with involvement of the peripheral nerve system, kidney and symptoms from ear, nose and throat [4], [6].\n\nThe prognosis of EGPA can be assessed with the five factor score system (FFS), where the presence of each of the following is given 1 point: 1) Cardiac involvement 2) Gastrointestinal involvement 3) Renal insufficiency 4) Proteinuria 5) Central Nervous system involvement [6]. Patients with a FSS from 0 usually achieves remission on systemic glucocorticoid treatment, and when the symptoms are under control, a reduction is recommended. With a FFS ≥1 the typical treatment is a combination of systemic glucocorticoids and cyclophosphamide, either once a month or daily. The duration remains controversial. The patient presented was given a combination of systemic glucocorticoids and cyclophosphamide.\n\nThe subgroup of EGPA patients with negative ANCA status and with cardiomyopathy had the poorest prognosis [4] and the prognosis was also worst for patients with endocarditis [3]. This emphasizes the importance of avoiding delay in the diagnostic process and initiation of treatment.\n\n7 Conclusion\nIn conclusion, this case emphasizes the importance of considering other causes of chest pain in a patient with a low risk profile and an atypical presentation. In particular, the development of neurological symptoms simultaneously with cardial symptoms on a background of severe asthma should prompt a suspicion of EGPA.• Chest pain and TnI elevations in a patient without risk factors for ischemic heart disease should lead to considerations regarding alternative diagnoses.\n\n• In a patient with late-onset eosinophilic asthma, development of extrapulmonary organ manifestations, including symptoms of vasculitis and neuritis, should lead to a suspicion of EGPA.\n\n• Fast and correct diagnosis and initiation of treatment is important to prevent permanent injury, and may prevent lethal outcomes\n\n\n\nFig. 1 High Resolution Computed axial Tomography scan showed peribronchial consolidated infiltrates bilaterally as well as small nodules (1a–c) and areas with subpleural ground glass attenuation in the right lower lobe (1d). Compared to the previous CT scan of the heart, there was now an increased size of the heart, and pericardial effusion.\n\nFig. 1\n==== Refs\nReferences\n1 Groh M. Pagnoux C. Baldini C. Bel E. Bottero P. Cottin V. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management Eur. J. Intern Med. 26 2015 545 553 25971154 \n2 Masi A.T. Hunder G.G. Lie J.T. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis) Arthritis Rheum. 33 1990 1094 1990 \n3 Neumann T. Manger B. Schmid M. Cardiac Involvement in churg-strauss syndrome Medicine 88 2009 236 243 19593229 \n4 Comarmond C. Pagnoux C. Khellaf M. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group Cohort Arthritis Rheum. 65 2013 270 281 23044708 \n5 Ali A.K. Hartzema A. Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting J. Asthma Allergy 5 2012 1 9 22690127 \n6 Sablé-Fourtassou R. Mahr A. Pagnoux C. Antineutrophil cytoplasmatic antibodies and the churg-strauss syndrome Ann. Intern. Med. 143 2005 632 638 16263885 \n7 Rosenberg M. Lorenz Gassler N. Rapid progressive eosinophilic cardiomyopathy in a patient with churg-strauss syndrome (CSS) Clin. Res. Cardiol. 95 2006 289 294 16598400 \n8 Sidhu B. Nanda U. Abbas S. Is this an exacerbation of asthma? a cautionary tale BMJ Case Rep. 2013 \n9 Ungprasert P. Cheungpasitporn W. Is it acute coronary syndrome or churg-strauss syndrome? Am. J. Emerg. Med. 31 2013 270.e5-270.e8 \n10 Kakuoros N. Bastiaenen R. Kourliouros A. Anderson L. Churg-Strauss presenting as acute coronary syndrome: sometimes it's zebras BMJ Case Rep. 2011\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "19()", "journal": "Respiratory medicine case reports", "keywords": "Acute chest pain; Asthma; EGPA; Eosinophilic granulomatosis with polyangiitis", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "94-7", "pmc": null, "pmid": "27625985", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "24072836;25971154;22690127;16598400;19593229;22809775;23044708;16263885;2202307;22700996", "title": "Think twice - Diagnostic delay in a patient with acute chest pain.", "title_normalized": "think twice diagnostic delay in a patient with acute chest pain" }	[ { "companynumb": "DK-HORIZON-PRE-0295-2016", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "THEOPHYLLINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THEOPHYLLINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202020", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMALIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMALIZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MONTELUKAST SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MONTELUKAST" } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symptom masked", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BANG CL, PORSBJERG CM. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMALIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMALIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MONTELUKAST SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MONTELUKAST" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THEOPHYLLINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THEOPHYLLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomegaly", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BANG CL, PORSBJERG CM. THINK TWICE - DIAGNOSTIC DELAY IN A PATIENT WITH ACUTE CHEST PAIN. RESPIRATORY MEDICINE CASE REPORTS. 2016;19:94-7", "literaturereference_normalized": "think twice diagnostic delay in a patient with acute chest pain", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20161010", "receivedate": "20160915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12754682, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "Inhibitors of tumor necrosing factor alpha (TNF-a) have proven to be highly effective in the treatment of rheumatoid arthritis (RA). Concerns, however, are raised about the possible association between these treatments and an increased development of malignancies. The objective of this paper was to compare the risk of hematologic and solid malignancies in patients treated for RA with anti-TNF therapy, with the risk in the general population. From January 2000 until January 2012, all RA patients that started treatment with anti-TNF agents were included in this single-center cohort study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. In our cohort of 365 patients, 34 malignancies were discovered in 30 patients after the start of anti-TNF treatment; 20 patients developed a solid malignancy, 6 a hematologic, 2 a solid and a hematologic malignancy, and 2 patients developed 2 solid malignancies. The overall incidence rate (IR) of malignancy was 1379.1 per 100.000 patient years. The risk or standardized incidence ratio (SIR) of solid malignancy, calculated by comparison with the age-adjusted population in Flanders, was 120.1 in female and 136.7 in male patients. The calculated SIR of hematologic malignancy was 450.8 for women and 473.9 for men. Some immune modulation-related lymphoproliferative disorders regressed spontaneously when stopping TNF blockers. Overall, the malignancy risk in our rheumatoid arthritis patients treated with anti-TNF therapy was slightly higher than in the normal population; the risk of hematologic malignancies was more important.", "affiliations": "Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. nathaliebergh@hotmail.com.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. laure-anne@teuwen.com.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. rene.westhovens@uzleuven.be.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.verschueren@uzleuven.be.", "authors": "Berghen\|Nathalie\|N\|;Teuwen\|Laure-Anne\|LA\|;Westhovens\|Rene\|R\|;Verschueren\|Patrick\|P\|", "chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept", "country": "Germany", "delete": false, "doi": "10.1007/s10067-015-3026-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0770-3198", "issue": "34(10)", "journal": "Clinical rheumatology", "keywords": "Cyclic citrullinated peptide; Malignancies; Rheumatoid arthritis; TNF-a", "medline_ta": "Clin Rheumatol", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015897:Comorbidity; D000068800:Etanercept; D005260:Female; D006801:Humans; D015994:Incidence; D000069285:Infliximab; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011446:Prospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult", "nlm_unique_id": "8211469", "other_id": null, "pages": "1687-95", "pmc": null, "pmid": "26219489", "pubdate": "2015-10", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "17922666;16508929;8051534;22357455;22241900;17469100;21701623;21570495;20870100;22766000;22945500;21572154;16705109;15547182;23560463;11961039;21701636;20064207;19767727;19147611;23442063;21898354;18433475;18378514;21148156;16947774;20810498;22166850;18155297;12687538;18853167;17729297;21885875;10071343", "title": "Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study.", "title_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study" }	[ { "companynumb": "BE-JNJFOC-20151010073", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematological malignancy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm malignant", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGHEN N, TEUWEN L, WESTHOVENS R, VERSCHUEREN P. MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY. CLIN RHEUMATOL 2015?34 (10):1687-1695.", "literaturereference_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151021", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11649342, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "PHHY2015BE156486", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenocarcinoma of colon", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2001" } }, "primarysource": { "literaturereference": "BERGHEN N, TEUWEN L-A, WESTHOVENS R, VERSCHUEREN P.. MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY.. CLIN-RHEUMATOL. 2015?34(10):1687-95", "literaturereference_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151204", "receivedate": "20151204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11803202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "BE-JNJFOC-20151011513", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Non-Hodgkin^s lymphoma", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGHEN N, TEUWEN L, WESTHOVENS R, VERSCHUEREN P. MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY. CLIN RHEUMATOL 2015?34 (10):1687-1695.", "literaturereference_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151019", "receivedate": "20151019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11641432, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "PHHY2015BE158372", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2000", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Non-small cell lung cancer", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2002" } }, "primarysource": { "literaturereference": "BERGHEN N, TEUWEN L-A, WESTHOVENS R, VERSCHUEREN P.. MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY.. CLIN-RHEUMATOL. 2015?34(10):1687-95", "literaturereference_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151207", "receivedate": "20151207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11809031, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]
{ "abstract": "BACKGROUND\nMirabegron, a β3 adrenergic receptor agonist, is FDA approved for treatment of overactive bladder. Approved in 2012 in the US, there have been no reports of any effects of mirabegron on pulmonary function.\n\n\nMETHODS\nWe report the case of a 65 year old male with a history of Parkinson's disease, OSA, and aspiration pneumonia presenting with subacute worsening dyspnea and found to have worsening restrictive ventilatory defect with a pattern consistent with neuromuscular weakness. After recalling that initiation of mirabegron correlated with onset of his worsening symptoms, the patient decided to perform a trial period off the drug. He subsequently reported prompt improvement in his respiratory symptoms, which was confirmed objectively by pulmonary function tests. In this case, mirabegron was temporally associated with subacute worsening of the patient's pulmonary restrictive physiology, with subsequent resolution after discontinuation of the medication.\n\n\nCONCLUSIONS\nThe mechanism of this adverse effect is unknown, but we speculate that this effect may be potentially mediated by the effect of β3 adrenergic receptor agonism on skeletal muscle, in this case in a patient with pre-existing neuromuscular disease. Careful assessment of patients who develop shortness of breath while on mirabegron should include an assessment for restrictive lung disease secondary neuromuscular dysfunction. Additional study is needed of the effects of β3 agonism on skeletal muscle.", "affiliations": "Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 676 North St. Clair, Arkes Pavilion Suite 1400 Chicago, IL 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-341, Chicago, IL 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USA.", "authors": "Malsin\|Elizabeth S\|ES\|;Coleman\|John M\|JM\|;Wolfe\|Lisa F\|LF\|;Lam\|Anna P\|AP\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2019.02.012", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30003-610.1016/j.rmcr.2019.02.012Case ReportRespiratory dysfunction following initiation of mirabegron: A case report Malsin Elizabeth S. Elizabeth.malsin@northwestern.edua∗Coleman John M. colemanjm@northwestern.edubWolfe Lisa F. lwolfe@northwestern.educLam Anna P. lam4@northwestern.eduaa Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USAb Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 676 North St. Clair, Arkes Pavilion Suite 1400 Chicago, IL 60611, USAc Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-341, Chicago, IL 60611, USA∗ Corresponding author. Elizabeth.malsin@northwestern.edu16 2 2019 2019 16 2 2019 26 304 306 4 1 2019 12 2 2019 15 2 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background: Mirabegron, a β3 adrenergic receptor agonist, is FDA approved for treatment of overactive bladder. Approved in 2012 in the US, there have been no reports of any effects of mirabegron on pulmonary function.\n\nCase presentation: We report the case of a 65 year old male with a history of Parkinson's disease, OSA, and aspiration pneumonia presenting with subacute worsening dyspnea and found to have worsening restrictive ventilatory defect with a pattern consistent with neuromuscular weakness. After recalling that initiation of mirabegron correlated with onset of his worsening symptoms, the patient decided to perform a trial period off the drug. He subsequently reported prompt improvement in his respiratory symptoms, which was confirmed objectively by pulmonary function tests. In this case, mirabegron was temporally associated with subacute worsening of the patient's pulmonary restrictive physiology, with subsequent resolution after discontinuation of the medication.\n\nConclusions: The mechanism of this adverse effect is unknown, but we speculate that this effect may be potentially mediated by the effect of β3 adrenergic receptor agonism on skeletal muscle, in this case in a patient with pre-existing neuromuscular disease. Careful assessment of patients who develop shortness of breath while on mirabegron should include an assessment for restrictive lung disease secondary neuromuscular dysfunction. Additional study is needed of the effects of β3 agonism on skeletal muscle.\n\nKeywords\nNeuromuscular lung diseaseAdverse medication effectβ3 receptor agonist therapy\n==== Body\n1 Background\nMirabegron is a β3-adrenergic receptor agonist prescribed for overactive bladder. While several β3 agonists have been developed, only mirabegron is FDA approved. The most commonly reported adverse effects of mirabegron include hypertension, tachycardia, headache, dizziness, constipation, diarrhea, abdominal pain, back pain, arthralgias and sinusitis. The only pulmonary complication reported was development of a pulmonary neoplasm. We report a case of a patient who developed restrictive ventilatory defect following the initiation of mirabegron.\n\n2 Case presentation\nOur patient is a 65 year-old man with a history of Parkinson's disease, obstructive sleep apnea on CPAP, and aspiration pneumonia. His medications include mirabegron, finasteride, pramipexole, albuterol as needed, modafinil, carbidopa-levodopa, metformin, multivitamins, and ibuprofen as needed. In July 2017, he presented with increased dyspnea on exertion. He noted worsening dyspnea for several weeks, with progression to dyspnea with activities of daily living. He denied constitutional symptoms, including changes in his physical strength, muscle spasms or worsening tremor. His vital signs were unremarkable; exam was notable for mild diaphoresis and dyspnea at rest, but a normal lung exam.\n\nPulmonary function tests (PFT) revealed decline in seated forced expiratory volume in 1 s (FEV1) to 3.10 L (78% predicted) from 4.13 L (92%) two years prior; decline in forced vital capacity (FVC) 3.79 L (72%) from 4.95 L (102%); FEV1/FVC ratio 82%, and total lung capacity (TLC) 7.17L (90%, from 7.99L (105%)), with a normal diffusion capacity of carbon monoxide (DLco) of 26.9 mL/mmHg/minute (93%). Also notable were supine FVC 3.43L (65%) and FEV1 2.72 L (69%). Seated maximal inspiratory pressure (MIP) was 69 cm H2O (64%) and maximal expiratory pressure (MEP) was 77 (38%). High-resolution computed tomography scan of the chest showed ground glass opacities in the right lower lobe, stable 3 mm nodule in the left lower lobe, and stable moderate air trapping. The patient was initiated on a bronchial hygiene regimen and sent for follow-up with his neurologist given concern for the patient's Parkinson's disease contributing to new onset neuromuscular respiratory disease, given the pattern of limitation on his PFT.\n\nHis dyspnea persisted the following month. After viewing a television commercial for mirabegron warning of possible adverse effect of shortness of breath (due to anaphylaxis), the patient correlated initiation of mirabegron for urinary urgency with the start of his symptoms, and self-discontinued his mirabegron. He returned to clinic six weeks later and reported subjective improvement of his dyspnea. His urinary urgency was noted to be at previous baseline and was deemed tolerable by the patient. He again noted no other changes to his baseline Parkinson's symptoms.\n\nOffice spirometry demonstrated increases in supine FEV1 to 4.73 mL (+13%) and maximal expiratory pressure to 102 cm (+24%). Four months later, FVC improved to 4.09L (78%) and TLC to 7.94L (108%). While the temporal relationship between the use and discontinuation of mirabegron with the patient's symptoms and change in lung function suggests respiratory muscle pathology without symptoms of simultaneous non-respiratory muscle weakness, the mechanism by which β3-adrenergic receptor agonism could cause respiratory dysfunction has not been described.\n\n3 Discussion\nAfter caring for this patient, the authors reviewed the known physiology and pathology, as well as the literature, regarding potential mechanisms behind the development of symptomatic neuromuscular respiratory illness after the initiation of mirabegron. To our knowledge, there is no report in the literature of this potential adverse effect. However, our review did identify potential pathophysiologic mechanisms.\n\nThree known subtypes of β-adrenergic receptors (β-AR) exist, with the β3-adrenergic receptor (ADRB3) found in multiple tissues and constituting the predominant β-AR in the detrusor muscles of the bladder [1,2]. From RNA-Sequencing analysis and the Human Protein Atlas (dataset, highest expression levels of ADRB3 are in the ovary at 10 transcripts per million (TPM), gallbladder (2.6 TPM), and smooth muscle (1.4 TPM). Other tissues have minimal expression, including lung tissue (0.1 TPM) and skeletal muscle (0 TPM) [3,4]. However, immunostaining using the high-affinity monoclonal antibody Mab72c demonstrates β3-receptors in skeletal muscle, adipose tissue, and myocardial tissue [5].\n\nβ1-and β2-adrenergic receptors, Gs-linked receptors, when activated by catecholamines mediate a rise in cyclic-AMP resulting in activation of protein kinase A [6,7]. Multiple studies have demonstrated a different mechanism for the β3-AR, including activity via the mTOR and Gi-nitric oxide synthetase (NOS) pathways [8,9]. Studies revealing stimulation of β-AR in skeletal muscle produces anabolic effects, likely via a crucial role in protein metabolism, have spurred interest in the therapeutic potential of β-AR agonists in muscular pathologies [[10], [11], [12]]. Puzzo and colleagues demonstrated β3-receptor agonism significantly increases muscle force production and myofiber area, and decreases muscle fiber stiffness [13], similar to previous reports of β2-AR agonism, in fast-twitch fibers [14]. The novel finding that β3-agonism decreased stiffness of muscle fibers has potential implications for diseases with high muscle stiffness, including muscle dystrophies.\n\nThe majority of patients with Parkinson's disease have muscle rigidity, which can affect any skeletal muscle. Baclofen, a gamma-aminobutyric acid (GABA)-receptor agonist, is used to treat spasticity and dystonia in Parkinson's disease. Hypotonia is the most common adverse reaction, occurring in 2.4–34.7% of patients receiving intrathecal baclofen during trials [15]. Muscular weakness has also been reported in patients on oral baclofen for spasticity [16,17]. Baclofen impacts control of ventilation and can cause central apnea events [18], with overdose reported to cause flaccid paralysis and respiratory depression [19,20].\n\nIn our patient with Parkinson's disease, we speculate β3-agonism of mirabegron may have had similar effects as baclofen overdose and may have acted synergistically with baclofen, resulting in decreased stiffness of respiratory muscles and worsened lung function. In light of the findings of Puzzo et al., [13] further research is needed to elucidate effects of β3-AR agonism in muscles, and mirabegron should be closely monitored in patients with neurodegenerative and neuromuscular diseases.\n\nEthics approval\nNot applicable.\n\nConsent for publication\nObtained from patient (adult).\n\nAvailability of data and materials\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nConflicts of interest\nThe authors declare that they have no competing interests.\n\nAuthor contributions\nESM, JMC, AIL analyzed and interpreted patient data. ESM wrote the manuscript with JMC, AIL, LFW contributing equally to its final form. All authors read and approved the final manuscript.\n\nFunding\nDr. Malsin is funded in part via NIH institutional T32 –HL076139.\n\nAbbreviations:\nPFTpulmonary function tests\n\nFEV1forced expiratory volume in one second\n\nFVCforced vital capacity\n\nFEV1/FVCratio of forced expiratory volume in 1 s to forced vital capacity\n\nTLCtotal lung capacity\n\nDLcodiffusion capacity of carbon monoxide\n\nMIPmaximal inspiratory pressure\n\nMEPmaximal expiratory pressure\n\nβ-ARβ-adrenergic receptors\n\nTPMtranscripts per million\n\nGABAgamma-aminobutyric acid\n\n\n\nAcknowledgements\nnot applicable.\n==== Refs\nReferences\n1 Igawa Y. Aizawa N. Homma Y. Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder Kor. J. Urol. 51 12 2010 811 818 \n2 Ochodnicky P. Uvelius B. Andersson K.E. Michel M.C. Autonomic nervous control of the urinary bladder Acta Physiol. (Oxf). 207 1 2013 16 33 23033838 \n3 Fagerberg L. Hallstrom B.M. Oksvold P. Kampf C. Djureinovic D. Odeberg J. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics Mol. Cell. Proteomics 13 2 2014 397 406 24309898 \n4 Uhlen M. Oksvold P. Fagerberg L. Lundberg E. Jonasson K. Forsberg M. Towards a knowledge-based human protein Atlas Nat. Biotechnol. 28 12 2010 1248 1250 21139605 \n5 Chamberlain P.D. Jennings K.H. Paul F. Cordell J. Berry A. Holmes S.D. The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle Int. J. Obes. Relat. Metab. Disord. 23 10 1999 1057 1065 10557026 \n6 Strosberg A.D. Structure, function, and regulation of adrenergic receptors Protein Sci. 2 8 1993 1198 1209 8401205 \n7 Wachter S.B. Gilbert E.M. 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Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action J. Anim. Sci. 76 1 1998 160 172 9464897 \n13 Puzzo D. Raiteri R. Castaldo C. Capasso R. Pagano E. Tedesco M. CL316,243, a beta3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength Sci. Rep. 5 2016 37504 27874066 \n14 Zeman R.J. Ludemann R. Easton T.G. Etlinger J.D. Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a beta 2-receptor agonist Am. J. Physiol. 254 6 Pt 1 1988 E726 E732 3377073 \n15 Lioresal (Baclofen) Injection Package Insert 2016 Saol Therapeutics, Inc. Roswell, GA \n16 Baclofen Tablet Package Insert 2016 Lannett Company, Inc. Philadelphia, PA \n17 Dario A. Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity Drug Saf. 27 11 2004 799 818 15350152 \n18 Olivier P.Y. Joyeux-Faure M. Gentina T. Launois S.H. d'Ortho M.P. Pepin J.L. Severe central sleep apnea associated with chronic baclofen therapy: a case series Chest 149 5 2016 e127 e131 27157226 \n19 Caron E. Morgan R. Wheless J.W. An unusual cause of flaccid paralysis and coma: baclofen overdose J. Child Neurol. 29 4 2014 555 559 23481445 \n20 Stroud J. Scattoloni J. Blasingim M. Nafiu O.O. Intrathecal baclofen toxicity: an unusual cause of paediatric postoperative coma and respiratory depression Eur. J. 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRABEGRON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FINASTERIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MODAFINIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MODAFINIL." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory muscle weakness", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lung disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MALSIN ES, COLEMAN JM, WOLFE LF, LAM AP. RESPIRATORY DYSFUNCTION FOLLOWING INITIATION OF MIRABEGRON: A CASE REPORT. RESPIRAT-MED-CASE-REPORT 2019?26:304-306.", "literaturereference_normalized": "respiratory dysfunction following initiation of mirabegron a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190409", "receivedate": "20190409", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16173449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-MYLANLABS-2019M1028283", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL /00139501/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MODAFINIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MODAFINIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIRABEGRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MICTURITION URGENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRABEGRON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINASTERIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FINASTERIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRAMIPEXOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAMIPEXOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "209594", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Respiratory disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MALSIN ES, COLEMAN JM, WOLFE LF, LAM AP. RESPIRATORY DYSFUNCTION FOLLOWING INITIATION OF MIRABEGRON:A CASE REPORT. RESPIRAT-MED-CASE-REPORT 2019?26:304-306.", "literaturereference_normalized": "respiratory dysfunction following initiation of mirabegron a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190328", "receivedate": "20190328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16131190, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "Women with epilepsy have a higher risk of having dysmorphic child. We report on a child exposed prenatally to valproate and carbamazepine presenting with severe bilateral upper limb defect and phenotypic features of fetal valproate syndrome. Anticonvulsant drugs can cause severe birth defects, especially when used in combination.", "affiliations": "Department of Obstetrics and Gynecology, Kahramanmaras Sutcuimam University, Turkey. mguven@ksu.edu.tr", "authors": "Guven\|Melih Atahan\|MA\|;Batukan\|Cem\|C\|;Ceylaner\|Serdar\|S\|;Ceylaner\|Gülay\|G\|;Uzel\|Murat\|M\|", "chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid", "country": "England", "delete": false, "doi": "10.1080/14767050500420665", "fulltext": null, "fulltext_license": null, "issn_linking": "1476-4954", "issue": "19(2)", "journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians", "keywords": null, "medline_ta": "J Matern Fetal Neonatal Med", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D002220:Carbamazepine; D004827:Epilepsy; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital; D011247:Pregnancy; D014635:Valproic Acid", "nlm_unique_id": "101136916", "other_id": null, "pages": "115-7", "pmc": null, "pmid": "16676441", "pubdate": "2006-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of fetal anticonvulsant syndrome with severe bilateral upper limb defect.", "title_normalized": "a case of fetal anticonvulsant syndrome with severe bilateral upper limb defect" }	[ { "companynumb": "TR-ABBVIE-06P-161-0332583-00", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "018081", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Limb malformation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Limb hypoplasia congenital", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUVEN M, BATUKAN C, CEYLANDER S, ET AL. A CASE OF FETAL ANTICONVULSANT SYNDROME WITH SEVERE BILATERAL UPPER LIMB DEFECT. THE JOURNAL OF MATERNAL-FETAL AND NEONATAL MEDICINE. 2006 FEB;19(2):115-117.", "literaturereference_normalized": "a case of fetal anticonvulsant syndrome with severe bilateral upper limb defect", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "FR", "receiptdate": "20170705", "receivedate": "20170705", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13718647, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" } ]
{ "abstract": "BACKGROUND\nKoebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event.\n\n\nOBJECTIVE\nTo study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal.\n\n\nMETHODS\nWe assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR.\n\n\nRESULTS\nAll lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls.\n\n\nCONCLUSIONS\nWe observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.", "affiliations": "Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.", "authors": "Gambichler\|T\|T\|;Rüddel\|I\|I\|;Hessam\|S\|S\|;Bechara\|F G\|FG\|;Stockfleth\|E\|E\|;Schmitz\|L\|L\|", "chemical_list": "C540838:5-hydroxymethyl-2'-deoxycytidine; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D044503:5-Methylcytosine; C538784:IDH2, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000069462:Dimethyl Fumarate; D001379:Azathioprine", "country": "England", "delete": false, "doi": "10.1111/jdv.14887", "fulltext": null, "fulltext_license": null, "issn_linking": "0926-9959", "issue": "32(9)", "journal": "Journal of the European Academy of Dermatology and Venereology : JEADV", "keywords": null, "medline_ta": "J Eur Acad Dermatol Venereol", "mesh_terms": "D044503:5-Methylcytosine; D001379:Azathioprine; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D000069462:Dimethyl Fumarate; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007521:Isocitrate Dehydrogenase; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D009364:Neoplasm Recurrence, Local; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D012867:Skin; D012878:Skin Neoplasms; D012879:Skin Physiological Phenomena; D016159:Tumor Suppressor Protein p53", "nlm_unique_id": "9216037", "other_id": null, "pages": "1485-1491", "pmc": null, "pmid": "29478287", "pubdate": "2018-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery.", "title_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery" }	[ { "companynumb": "DE-MYLANLABS-2018M1068147", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA FG, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. J?EUR?ACAD?DERMATOL?VENEREOL 2018?32(9):1485?1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180924", "receivedate": "20180924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15417744, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "DE-BIOGEN-2017BI00458203", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 13 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte count decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neoplasm skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY. 2018?32(9):1485-1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181116", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13981984, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "DE-BIOGEN-2018BI00538186", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 13 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte count decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY + VENEREOLOGY.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180314", "receivedate": "20180314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14634674, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "DE-BIOGEN-2018BI00538183", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR OVER 15 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte percentage decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181116", "receivedate": "20180315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14642557, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "DE-MYLANLABS-2018M1068061", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA FG, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. J?EUR?ACAD?DERMATOL?VENEREOL 2018?32(9):1485?1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180925", "receivedate": "20180925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15423915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Colon and rectal lymphomas are rare and can occur in the context of posttransplant lymphoproliferative disorder. Evidence-based management guidelines are lacking.\n\n\n\nThe purpose of this study was to characterize the presentation, diagnosis, and management of colorectal lymphoma and to identify differences within the transplant population.\n\n\n\nThis was a retrospective review of patients evaluated for colorectal lymphoma between 2000 and 2017. Patients were identified through clinical note queries.\n\n\n\nFour hospitals within a single health system were included.\n\n\n\nFifty-two patients (64% men; mean age = 64 y; range, 26-91 y) were identified. No patient had <3 months of follow-up. Eight patients (15%) had posttransplant lymphoproliferative disorder.\n\n\n\nOverall survival, recurrence, and complications in treatment pathway were measured.\n\n\n\nMost common presentations were rectal bleeding (27%), abdominal pain (23%), and diarrhea (23%). The most common location was the cecum (62%). Most frequent histologies were diffuse large B-cell lymphoma (48%) and mantle cell lymphoma (25%). Posttransplant lymphoproliferative disorder occurred in the cecum (n = 4) and rectum (n = 4). Twenty patients (38%) were managed with chemotherapy; 25 patients (48%) underwent primary resection. Mass lesions had a higher risk of urgent surgical resection (35% vs 8%; p = 0.017). Three patients (15%) treated with chemotherapy presented with perforation requiring emergency surgery. Overall survival was 77 months (range, 25-180 mo). Patients with cecal involvement had longer overall survival (96 vs 26 mo; p = 0.038); immunosuppressed patients had shorter survival (16 vs 96 mo; p = 0.006). Survival in patients treated with surgical management versus chemotherapy was similar (67 vs 105 mo; p = 0.62).\n\n\n\nThis was a retrospective chart review, with data limited by the contents of the medical chart. This was a small sample size.\n\n\n\nColorectal lymphoma is rare, with variable treatment approaches. Patients with noncecal involvement and chronic immunosuppression had worse overall survival. Patients with mass lesions, particularly cecal masses, are at higher risk to require urgent intervention, and primary resection should be considered. See Video Abstract at http://links.lww.com/DCR/A929.", "affiliations": "Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Medical School, University of Minnesota, Minneapolis, Minnesota.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.;Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota.;Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Surgery, University of California Los Angeles, Los Angeles, California.", "authors": "Skube\|Steven J\|SJ\|;Arsoniadis\|Elliot G\|EG\|;Sulciner\|Megan L\|ML\|;Gilles\|Scott R\|SR\|;Gaertner\|Wolfgang B\|WB\|;Madoff\|Robert D\|RD\|;Melton\|Genevieve B\|GB\|;Peterson\|Bruce A\|BA\|;Kwaan\|Mary R\|MR\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/DCR.0000000000001373", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-3706", "issue": "62(6)", "journal": "Diseases of the colon and rectum", "keywords": null, "medline_ta": "Dis Colon Rectum", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "0372764", "other_id": null, "pages": "694-702", "pmc": null, "pmid": "30870226", "pubdate": "2019-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Colorectal Lymphoma: A Contemporary Case Series.", "title_normalized": 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{ "abstract": "Radiation therapy of neoplasms involving the chest or mediastinum results in a wide spectrum of cardiac complications including coronary artery disease, which can present in patients with few or no traditional cardiac risk factors. We report a case of radiation induced coronary artery disease in a 60-year-old female with a history of stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier and treated with chemotherapy and radiotherapy. She presented to the hospital with atypical chest pain that had occurred intermittently over the preceding week. Her initial electrocardiogram and cardiac enzymes were within normal limits. However, following an indeterminate exercise nuclear stress test, she developed chest pain and elevated cardiac enzymes. Coronary angiography demonstrated 90% stenosis of the left main coronary artery ostium, without any evidence of atherosclerotic disease or stenosis in other coronary arteries. She underwent surgical revascularization, which revealed dense adhesions surrounding the heart. During surgery, she developed severe bleeding and died. Coronary artery disease can present within years of radiation exposure, and ostial lesions are typical. Treatment is often challenging because of the effects of radiation on other tissues and the risks of revascularization procedures. Therefore, a multidisciplinary team approach should be considered.", "affiliations": "Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USA.", "authors": "Alsara\|Osama\|O\|;Alsarah\|Ahmad\|A\|;Kalavakunta\|Jagadeesh K\|JK\|;Laird-Fick\|Heather\|H\|;Abela\|George S\|GS\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2013/834164", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/834164Case ReportIsolated Left Main Coronary Artery Stenosis after Thoracic Radiation Therapy: To Operate or Not to Operate Alsara Osama \n1\nAlsarah Ahmad \n1\nKalavakunta Jagadeesh K. \n2\nhttp://orcid.org/0000-0001-9215-8152Laird-Fick Heather \n1\nAbela George S. \n2\n1Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA3Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USAOsama Alsara: osama.alsara@hc.msu.eduAcademic Editor: Bruno Megarbane\n\n2013 12 12 2013 2013 83416420 6 2013 6 11 2013 Copyright © 2013 Osama Alsara et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Radiation therapy of neoplasms involving the chest or mediastinum results in a wide spectrum of cardiac complications including coronary artery disease, which can present in patients with few or no traditional cardiac risk factors. We report a case of radiation induced coronary artery disease in a 60-year-old female with a history of stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier and treated with chemotherapy and radiotherapy. She presented to the hospital with atypical chest pain that had occurred intermittently over the preceding week. Her initial electrocardiogram and cardiac enzymes were within normal limits. However, following an indeterminate exercise nuclear stress test, she developed chest pain and elevated cardiac enzymes. Coronary angiography demonstrated 90% stenosis of the left main coronary artery ostium, without any evidence of atherosclerotic disease or stenosis in other coronary arteries. She underwent surgical revascularization, which revealed dense adhesions surrounding the heart. During surgery, she developed severe bleeding and died. Coronary artery disease can present within years of radiation exposure, and ostial lesions are typical. Treatment is often challenging because of the effects of radiation on other tissues and the risks of revascularization procedures. Therefore, a multidisciplinary team approach should be considered.\n==== Body\n1. Introduction\nFor the past few decades, radiation has been used effectively in the treatment of neoplasms involving the chest and mediastinum, including breast cancer, lymphomas, and lung cancer. However, radiotherapy of the chest can have a number of cardiac complications including pericarditis, pericardial effusions, conduction disorders, pancarditis, functional valvular defects, and coronary artery disease (CAD) [1]. CAD has been reported more commonly with Hodgkin's lymphoma, presumably because these patients tend to be younger and survive longer [2]. In this report we describe a 60-year-old woman with isolated left main coronary ostial stenosis diagnosed eight years after chest irradiation performed for stage IIIA nonsmall cell lung cancer. This case emphasizes the importance of clinical suspicion, prognostication, and the balancing risks and benefits of competing therapies.\n\n2. Case Presentation\nA 60-year-old woman with a history of lung cancer currently in remission was admitted with complaints of chest pain. She had recurrent substernal chest pain, increasing in severity, without radiation or associated symptoms during the preceding week. She denied any specific alleviating or provoking factors.\n\nPast medical history was significant for hypertension and stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier. She had been treated with chemotherapy and radiotherapy. One year later she developed a malignant pericardial effusion, treated with a pericardial window, and recurrent pleural effusions, which were drained with pleural catheters. During the next six years, she was in full remission as confirmed by annual chest computed tomography (CT). Her medications included aspirin, metoprolol, iron, vitamin B12, and gefitinib. She was a nonsmoker and drinks alcohol occasionally.\n\nAt presentation, her physical exam was benign. Initial cardiac biomarkers (creatine phosphokinase, troponin) and fasting lipid panel were within normal limits. The 12-lead electrocardiogram (ECG) showed normal sinus rhythm without any significant ST-T changes. Chest radiograph showed left perihilar parenchymal scars, surgical clips, and postoperative changes in the chest (Figure 1). Other laboratory studies, including two more sets of cardiac biomarkers, were normal.\n\nShe underwent an exercise nuclear stress test which demonstrated indeterminate electrocardiogram (ECG) changes with a small anteroseptal wall defect which appeared to be artifactual. Following the stress test, she developed retrosternal chest pain. Although her ECG did not show any acute changes, repeat serum troponin level was elevated at 0.42 ug/L. Coronary angiography was performed and demonstrated 90% stenosis of the left main coronary artery ostium, dominant right coronary artery, and no evidence of any atherosclerotic disease or stenosis in other coronary arteries (Figures 2, 3, and 4). Left ventricular ejection fraction was 55% without any regional wall motion abnormalities.\n\nSyntax score was calculated to be 12% which predicts comparable outcomes of surgical and angioplastic procedures. Taking into consideration patient's history that may complicate the surgical treatment including her previous surgical interventions, radiation therapy, and chemical therapy, the interventional cardiology team recommended percutaneous coronary intervention (PCI) with stenting of the lesion. Cardiothoracic surgeons were consulted as well for further evaluation and they agreed that surgery will be challenging in this patient, but at the same time they felt that she may tolerate the surgery well, given her functional status, remission from cancer, and the low operative risk (EuroScore is 1.23%), and they suggested coronary artery bypass graft (CABG) surgery as a reasonable option due to the high failure rate of stenting ostial lesions and to avoid the possible cardiac arrest associated with the intervention on the stenotic ostium of left main coronary artery.\n\nAfter discussing both treatment options, the risks and benefits of each procedure with the patient, she decided to undergo surgical revascularization. Overnight, she experienced excruciating anginal chest pain without any elevation in cardiac enzymes; as a result she was taken to surgery the next day.\n\nIntraoperatively she was noted to have dense adhesions surrounding the heart. As a result, she developed severe bleeding from the adhesions. Despite aggressive transfusion of red blood cells and platelets, bleeding could not be controlled and she died during surgery. The family refused to allow autopsy to confirm the diagnosis.\n\n3. Discussion\nThis is a case of a 60-year-old female with no classic cardiac risk factors, who developed a stenosis in the ostium of left main coronary artery eight years after undergoing radiation therapy for nonsmall cell lung cancer. She went to the operating room for CABG due to recurrent unstable angina but developed fatal bleeding related to side effects of both radiation and chemotherapy.\n\nThoracic irradiation can result in injury or inflammation of any of the cardiac structures. CAD has been reported in 5.5–12% of patients undergoing therapeutic chest radiotherapy, usually manifesting 3–30 years after radiation exposure [3]. Histology of coronary artery tissues obtained from affected patients have demonstrated intimal thickening with minimal extracellular lipid deposits [4]. Although the mechanism of radiation induced CAD (RICAD) is not fully understood, it is believed that radiation may stimulate cytokines and growth factors which in turn induce fibrosis and obstruction [5].\n\nOstial stenosis is typical of RICAD, since the vessels' openings are usually at the center of the radiation field. One study found that 16% of isolated coronary ostial stenosis was secondary to radiation therapy [6]. Isolated ostial stenosis of the left main coronary artery following radiation therapy has been reported in eight other cases in the literature [7–14] (Table 1). These patients were young to middle-aged females (mean age 40 years, range 26–51 years), with no or few traditional risk factors for CAD. Most presented with typical angina, between 2 and 20 years after radiotherapy. Our patient was older than those previously reported and developed symptoms eight years after therapy. Since RICAD presents about 16 years after radiation exposure and the 5 year survival life in patients with stage IIIA nonsmall cell lung cancer is estimated to be between 9 and 25%, it is very rare to see RICAD in this group [1, 15].\n\nThe strategy for revascularization of RICAD is typically the same as for atherosclerotic CAD [1]. Traditionally, CABG has been considered the treatment of choice for left main coronary artery disease (LMCAD) due to its role in increasing the life expectancy in patients with significant stenosis [16, 17]. The left internal mammary artery (LIMA) is typically used as a bypass conduit. Despite concerns that radiation might damage the LIMA, increase its fragility, and lead to early graft failure [18, 19], recent studies have documented patency rates comparable to that of venous grafts at 5 year follow-up [20, 21], making LIMA grafting a viable option for RICAD as well. Yet cardiac surgery in patients with past chest irradiation can still be technically challenging, with a greater risk of perioperative complications in the presence of pericardial thickening and retrosternal fibrosis. Although an early study has showed good outcomes of CABG treatments in patients with mediastinal radiation therapy, Wu et al. have found recently that patients with radiation induced heart disease have greater short-term and long-term mortality after cardiovascular surgeries compared to patients in same age and sex who underwent similar surgeries [22, 23]. This study also showed that the standard preoperative risk scores are usually suboptimal in predicting mortality of cardiac surgeries in patients with radiation heart disease [23]. With this in mind, other treatment options such as PCI should always be considered.\n\nThere is a growing body of literature supporting PCI with stenting of LMCAD due to atherosclerosis. Some trials have yielded rates of myocardial infarction and mortality similar to CABG, but with better perioperative outcomes [24]. As a result, PCI is now considered an acceptable alternative to surgical revascularization in some patients with LMCAD [16, 25, 26]. This approach could be particularly attractive for patients with radiation-induced adhesions. Ostial stents, though, have been associated with higher rates of restenosis related to their increased risk for proximal or distal displacement [27]. Several new techniques may improve the precision of ostial stent positioning [28], but long-term outcome data are not yet available.\n\nOther comorbidities or medications may also influence the decision to choose percutaneous or surgical revascularization in patients with RICAD. For example, our patient was receiving the gefitinib, a chemotherapeutic agent which decreases platelet function via prostaglandin and thrombaxene and increases the bleeding risk [29]. There are no guidelines or studies on the perioperative management of patients receiving gefitinib. Its half-life is 48 hours, in contrast to 8 hours for the more common antiplatelet agents such as clopidogrel, so prolonged interruption of therapy may be necessary to decrease bleeding risk. We believe that additional preoperative evaluation by a hematologist-oncologist is warranted. Balancing the risk of bleeding against the risk of myocardial infarction or death becomes a complicated and imprecise calculus requiring the input of a multidisciplinary team.\n\nOur case is unique, in that our patient was older at presentation, underwent chest irradiation for lung cancer rather than lymphoma, developed isolated left main coronary ostial stenosis, and her management was complicated by the combined effects of radiation and chemotherapy. More importantly, this case emphasizes the importance of a multidisciplinary team approach and participatory decision making when faced with significant risks of available treatment options.\n\nDisclosure\nDrs. Alsara, Kalavakunta, Alsarah, and Laird-Fick have no relationships to disclose. Dr. Abela is a speaker of Merck, Abbott, and GlaxoSmithKline. Those relationships are not related to this paper.\n\nAcknowledgment\nDr. Abela is a recipient of grants from Merck and Novartis.\n\nFigure 1 Posterior to anterior chest X-ray shows left perihilar parenchymal scars, surgical clips, and postoperative changes in the chest.\n\nFigure 2 Coronary angiography with a right anterior oblique (RAO)/caudal projection. Arrow points to severe isolated ostial stenosis of left main coronary artery.\n\nFigure 3 Coronary angiography of left main coronary artery in the left anterior oblique (LAO) and caudal view showing severe isolated ostial stenosis (arrow).\n\nFigure 4 Coronary angiography of the right coronary artery in left anterior oblique (LAO) view.\n\nTable 1 Review of reported cases of isolated ostial stenosis of left main coronary artery following radiation therapy.\n\nAuthors (year)\tGender\tAge (Y)\tRF\tNeoplasm\tLatency (Y)\tPresenting symptoms\t\nRadwaner et al. [7] (1987)\tF\t27\tNo\tHodgkin's lymphoma\t8\tAngina\t\nGrollier et al. [8] (1988)\tF\t50\tSmoking \tBreast cancer\t5\tAngina\t\nOrzan et al. [9] (1995)\tF\t26\tNo\tHodgkin's lymphoma\t10\tDyspnea, pleural effusion\t\nTakewa et al. [10] (1996)\tF\t45\t/\tThymic carcinoid\t3\tAngina\t\nBensaid et al. [11] (1998)\tF\t43\tNo\tHodgkin's lymphoma\t20\tMyocardial infarction \t\nCaus et al. [12] (1999)\tF\t47\tSmoking\tNH lymphoma\t3\tAngina\t\nVictor and Parente [13] (2004)\tF\t51\tDyslipidemia\tHodgkin's lymphoma\t2\tAngina\t\nKorosoglou et al. [14] (2012)\tF\t34\tNo\tNH lymphoma\t6\tAngina\t\nF: female, Y: years, RF: risk factors for coronary artery disease, and NH: non-Hodgkin's.\n\nThe case of Takewa et al. [10] is in Japanese. The case of Bensaid et al. [11] is in French.\n==== Refs\n1 Veeragandham RS Goldin MD Surgical management of radiation-induced heart disease Annals of Thoracic Surgery 1998 65 4 1014 1019 2-s2.0-0031947823 9564920 \n2 Konings AW Smit Sibinga CT Aarnoudse MW de Wit SS Lamberts HB Initial events in radiation-induced atheromatosis. II. Damage to intimal cells Strahlentherapie 1978 154 11 795 800 2-s2.0-0018143851 715813 \n3 Miltenyi Z Keresztes K Garai I Radiation-induced coronary artery disease in Hodgkin’s disease Cardiovascular Radiation Medicine 2004 5 1 38 43 15275631 \n4 Dragomanovits SI Lazopoulos GL Tzinieris IN Deliargyris EN Coronary artery disease following mediastinal irradiation Hellenic Journal of Cardiology 2007 48 3 181 183 2-s2.0-34548033279 17629183 \n5 Yusuf SW Sami S Daher IN Radiation-induced heart disease: a clinical update Cardiology Research and Practice 2011 2011 9 pages 317659 \n6 Pilliere R Luquel L Brun D Jault F Gandjbakhch I Bourdarias JP Stenosis of the ostium of the left main coronary artery after mediastinal radiotherapy: a case report Archives des Maladies du Coeur et des Vaisseaux 1991 84 6 869 872 2-s2.0-0026179669 1898223 \n7 Radwaner BA Geringer R Goldmann AM Schwartz MJ Kemp HG Jr. Left main coronary artery stenosis following mediastinal irradiation American Journal of Medicine 1987 82 5 1017 1020 2-s2.0-0023614871 3578337 \n8 Grollier G Commeau P Mercier V Post-radiotherapeutic left main coronary ostial stenosis: clinical and histological study European Heart Journal 1988 9 5 567 570 2-s2.0-0023915199 3402473 \n9 Orzan F Bellis D Mollo F Brusca A Ostial stenosis of the left main coronary artery in a young woman 10 years after radiation therapy Cardiovascular Pathology 1995 4 1 69 71 2-s2.0-0028794975 25850782 \n10 Takewa Y Kawata T Yoshida Y Kawachi K Kitamura S Radiation-induced coronary ostial stenosis, a case of redo coronary bypass for the restenosis following patch angioplasty Nihon Kyobu Geka Gakkai Zasshi 1996 44 2 220 225 2-s2.0-0030080222 8717275 \n11 Bensaid J Benabbou M Goburdhun C Medard C Guillon A El Kenz A Ostial stenosis of the common trunk of the left coronary 20 years after mediastinal irradiation Annales de Cardiologie et d’Angeiologie 1998 47 10 732 734 2-s2.0-0032441956 \n12 Caus T Canavy I Mesana T Garcia E Raoul-Monties J Rescue revascularization for acute coronary occlusion late after radiotherapy Annals of Thoracic Surgery 1999 67 1 236 238 2-s2.0-0032989318 10086560 \n13 Victor EG Parente GB Mediastinal radiation therapy and occlusion of the ostium of the left main coronary artery Arquivos Brasileiros de Cardiologia 2004 82 3 295 300 2-s2.0-1642418088 15073656 \n14 Korosoglou G Kristen AV Andrassy M Katus HA Hardt SE Severe left main coronary stenosis in a young female patient, 6 years after mediastinal radiation therapy for non-Hodgkin lymphoma: assessment by coronary angiography and intravascular ultrasound Clinical Research in Cardiology 2012 101 4 317 320 2-s2.0-84856100084 22286318 \n15 Mountain CF Revisions in the international system for staging lung cancer Chest 1997 111 6 1710 1717 2-s2.0-0030912190 9187198 \n16 Wright RS Anderson JL Adams CD American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/Non–ST-elevation myocardial infarction : a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Journal of the American College of Cardiology 2011 57 19 e215 e367 2-s2.0-84860413284 21545940 \n17 Taggart DP Coronary artery bypass grafting is still the best treatment for multivessel and left main disease, but patients need to know Annals of Thoracic Surgery 2006 82 6 1966 1975 2-s2.0-33751233843 17126093 \n18 Hicks GL Jr. Coronary artery operation in radiation-associated atherosclerosis: long-term follow-up Annals of Thoracic Surgery 1992 53 4 670 674 2-s2.0-0026575538 1554280 \n19 Schulman HE Korr KS Myers TJ Left internal thoracic artery graft occlusion following mediastinal radiation therapy Chest 1994 105 6 1881 1882 2-s2.0-0028222239 8205898 \n20 Gansera B Schmidtler F Angelis I Quality of internal thoracic artery grafts after mediastinal irradiation Annals of Thoracic Surgery 2007 84 5 1479 1484 2-s2.0-35348970414 17954049 \n21 Brown ML Schaff HV Sundt TM Conduit choice for coronary artery bypass grafting after mediastinal radiation Journal of Thoracic and Cardiovascular Surgery 2008 136 5 1167 1171 2-s2.0-56249133492 19026798 \n22 Handa N McGregor CGA Danielson GK Coronary artery bypass grafting in patients with previous mediastinal radiation therapy Journal of Thoracic and Cardiovascular Surgery 1999 117 6 1136 1143 2-s2.0-0032970363 10343262 \n23 Wu W Masri A Popovic ZB Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study Circulation 2013 127 14 1476 1484 23569119 \n24 Dubois C Dens J Sinnaeve P Results of percutaneous coronary intervention of the unprotected left main coronary artery in 143 patients and comparison of 30-day mortality to results of coronary artery bypass grafting American Journal of Cardiology 2008 101 1 75 81 2-s2.0-37349002738 18157969 \n25 Park SJ Kim YH Park DW Randomized trial of stents versus bypass surgery for left main coronary artery disease New England Journal of Medicine 2011 364 18 1718 1727 2-s2.0-79955739237 21463149 \n26 Buszman PE Kiesz SR Bochenek A Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization Journal of the American College of Cardiology 2008 51 5 538 545 2-s2.0-38549139564 18237682 \n27 Dishmon DA Elhaddi A Packard K Gupta V Fischell TA High incidence of inaccurate stent placement in the treatment of coronary aorto-ostial disease Journal of Invasive Cardiology 2011 23 8 322 326 2-s2.0-80051987022 21828393 \n28 Kwan TW James D Huang Y Liou M Wong S Coppola J Perfection of precise ostial stent placement Journal of Invasive Cardiology 2012 24 7 354 358 22781478 \n29 Kanazawa S Yamaguchi K Kinoshita Y Muramatsu M Komiyama Y Nomura S Gefitinib affects functions of platelets and blood vessels via changes in prostanoids balance Clinical and Applied Thrombosis/Hemostasis 2005 11 4 429 434 2-s2.0-27544499208 16244768\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2013()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "834164", "pmc": null, "pmid": "24416042", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": "9564920;18237682;21545940;21828393;18157969;9187198;22781478;1554280;22286318;10343262;3578337;3402473;17126093;10086560;8205898;8717275;17954049;19026798;21463149;23569119;15073656;9922851;21403872;25850782;1898223;17629183;16244768;15275631;715813", "title": "Isolated left main coronary artery stenosis after thoracic radiation therapy: to operate or not to operate.", "title_normalized": "isolated left main coronary artery stenosis after thoracic radiation therapy to operate or not to operate" }	[ { "companynumb": "US-BAYER-2017-238058", 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{ "abstract": "A heavily pretreated patient with triple negative breast cancer distinguished by cutaneous metastases received p53MVA vaccine in combination with pembrolizumab. Her cutaneous metastases regressed and after 2 cycles of therapy, a skin biopsy showed a complete pathological response. Systemic response was confirmed with restaging CT and bone scans. Activation of p53-specific T cell responses and elevation of multiple immune response genes in peripheral blood correlated with the rapid clinical response which lasted for 6 months after the initiation of combined therapy.", "affiliations": "Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Research Operations, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Research Operations, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.", "authors": "Yuan\|Yuan\|Y\|;Kos\|Ferdynand J\|FJ\|;He\|Ting-Fang\|TF\|;Yin\|Hongwei H\|HH\|;Li\|Mengsha\|M\|;Hardwick\|Nicola\|N\|;Zurcher\|Kathryn\|K\|;Schmolze\|Daniel\|D\|;Lee\|Peter\|P\|;Pillai\|Raju K\|RK\|;Chung\|Vincent\|V\|;Diamond\|Don J\|DJ\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/2162402X.2017.1363138", "fulltext": null, "fulltext_license": null, "issn_linking": "2162-4011", "issue": "6(12)", "journal": "Oncoimmunology", "keywords": "MVA; PD-1; T cell response; immunotherapy; p53; pembrolizumab; triple negative breast cancer; vaccine; vaccinia", "medline_ta": "Oncoimmunology", "mesh_terms": null, "nlm_unique_id": "101570526", "other_id": null, "pages": "e1363138", "pmc": null, "pmid": "29209571", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "28280247;27079802;20182602;22713868;23948975;25941580;25242720;23462680;24987057;22495314;16391808;27138582;23000897;17219151;10676655;21843052;27184417;28280249;24764583;28228704", "title": "Complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53MVA vaccine with pembrolizumab.", "title_normalized": "complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53mva vaccine with pembrolizumab" }	[ { "companynumb": "US-DRREDDYS-USA/USA/17/0095482", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO SKIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201509", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Back pain", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2015" } }, "primarysource": { "literaturereference": "YUAN Y, KOS F, HE T, YIN H, LI M, HARDWICK N, ET AL. COMPLETE REGRESSION OF CUTANEOUS METASTASES WITH SYSTEMIC IMMUNE RESPONSE IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER RECEIVING P53MVA VACCINE WITH PEMBROLIZUMAB. ONCOIMMUNOLOGY. 2017?6 (12):.", "literaturereference_normalized": "complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53mva vaccine with pembrolizumab", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180212", "receivedate": "20180212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14520577, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "US-CIPLA LTD.-2017US30669", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERIBULIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201501", "drugenddateformat": "610", "drugindication": "METASTASES TO SKIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201402", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERIBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IXABEPILONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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COMPLETE REGRESSION OF CUTANEOUS METASTASES WITH SYSTEMIC IMMUNE RESPONSE IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER RECEIVING P53MVA VACCINE WITH PEMBROLIZUMAB. ONCOIMMUNOLOGY. 2017?6(12)", "literaturereference_normalized": "complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53mva vaccine with pembrolizumab", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180105", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14353848, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.", "affiliations": "Department of Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA, 94611, USA.;Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA.;Department of Orthopedic Surgery, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.;Department of Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA, 94611, USA. Joan.C.Lo@kp.org.", "authors": "Gu\|K D\|KD\|;Ettinger\|B\|B\|;Grimsrud\|C D\|CD\|;Lo\|J C\|JC\|http://orcid.org/0000-0002-7159-0648", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates", "country": "England", "delete": false, "doi": "10.1007/s00198-021-05948-w", "fulltext": null, "fulltext_license": null, "issn_linking": "0937-941X", "issue": "32(10)", "journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA", "keywords": "Atypical femur fracture; Bisphosphonate; Stress; Teriparatide", "medline_ta": "Osteoporos Int", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005269:Femur; D015775:Fractures, Stress; D006801:Humans", "nlm_unique_id": "9100105", "other_id": null, "pages": "2119-2123", "pmc": null, "pmid": "33914104", "pubdate": "2021-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy.", "title_normalized": "progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy" }	[ { "companynumb": "US-ORGANON-O2105USA001986", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM CITRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1800 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CITRATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "020560", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "70 MILLIGRAM PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOPENIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSAMAX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESTROGENS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.45 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENOPAUSAL SYMPTOMS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".45", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESTROGEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2000 IU/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LO JC, GU KD, ETTINGER B, GRIMSRUD CD.. 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"drugstartdateformat": null, "drugstructuredosagenumb": "2000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rebound effect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Wrist fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atypical fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Osteoporotic fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GU KD, ETTINGER B, GRIMSRUD CD, LO JC. PROGRESSION OF ATYPICAL FEMUR STRESS FRACTURE AFTER DISCONTINUATION OF BISPHOSPHONATE THERAPY. OSTEOPOROS?INT 2021?:.", "literaturereference_normalized": "progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210617", "receivedate": "20210617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19433141, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nPulmonary arterial hypertension (PAH), is a rare manifestation of systemic lupus erythematosus (SLE), characterized by pulmonary arterial remodeling leading to right ventricular failure and death. To date, optimal management of SLE-associated PAH should be clarified, especially regarding the respective places of immunosuppressants and PAH vasodilator treatments.\n\n\nMETHODS\nWe report the case of a 48-year-old woman with SLE and secondary Sjogren syndrome, associated with severe PAH and lupus peritonitis with massive ascites, who showed a remarkable response, both for SLE flare and PAH, to a treatment combining immunosuppressants and pulmonary arterial vasodilator treatment.\n\n\nCONCLUSIONS\nThis observation highlights the interest of combining immunosuppressive therapy in SLE-PAH, whose modalities in association with PAH treatments should be clarified.", "affiliations": "Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Physiologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.", "authors": "Yucel\|H\|H\|;Vollmer\|O\|O\|;Canuet\|M\|M\|;Enache\|I\|I\|;Kessler\|R\|R\|;Korganow\|A S\|AS\|;Riou\|M\|M\|https://orcid.org/0000-0001-6807-8582", "chemical_list": "D007166:Immunosuppressive Agents; D014665:Vasodilator Agents", "country": "England", "delete": false, "doi": "10.1177/0961203320976982", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "30(3)", "journal": "Lupus", "keywords": "Systemic lupus erythematosus; ascites; lupus peritonitis; pulmonary arterial hypertension", "medline_ta": "Lupus", "mesh_terms": "D001201:Ascites; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D000081029:Pulmonary Arterial Hypertension; D012859:Sjogren's Syndrome; D014665:Vasodilator Agents", "nlm_unique_id": "9204265", "other_id": null, "pages": "510-513", "pmc": null, "pmid": "33655792", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary Sjogren's syndrome.", "title_normalized": "severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary sjogren s syndrome" }	[ { "companynumb": "FR-JNJFOC-20210659752", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TADALAFIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200630", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pulmonary arterial hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201801", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TADALAFIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pulmonary arterial hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRACLEER" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "125 MILLIGRAM, QD/ START DATE:29-JUN-2018", "drugenddate": null, "drugenddateformat": null, 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"drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peritonitis lupus", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Yucel H.. Severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary Sjogren?s syndrome. 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MICROGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROX" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peritonitis lupus", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 202001" } }, "primarysource": { "literaturereference": "YUCEL H.. SEVERE PULMONARY ARTERIAL HYPERTENSION AND MASSIVE ASCITES IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND SECONDARY SJOGREN?S SYNDROME.. LUPUS.. 2021?30 (3)::510?513.", "literaturereference_normalized": "severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary sjogren s syndrome", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210922", "receivedate": "20210717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19573411, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "BACKGROUND\nPiroxicam is a widely used anti-inflammatory drug. Most adverse reactions affect gastrointestinal system, liver and skin. Fixed drug eruption although very unusual, has also been described, but with cutaneous involvement exclusively. We present the case of a 49-year-old man who suffered three episodes of fixed drug eruption with cutaneous-mucosal involvement, even simulating an autoimmune disease, whenever he was treated with oral piroxicam.\n\n\nRESULTS\nHe was patch tested on normal skin with the GEIDC standard series and an NSAIDs series. He was patch tested on normal skin and on fixed eruption with piroxicam, meloxicam and tenoxicam (all of them 1 % pet). Oral challenge test was not performed due to the severity and reproducibility in previous reactions. Results showed a positive patch test to piroxicam (1 % pet) on fixed eruption, with negative results to the rest.\n\n\nCONCLUSIONS\nAdverse drug reactions may present a wide variability of clinical symptoms. In these situations an accurate clinical history is necessary. To our knowledge this is the 1st report of non-pigmenting fixed drug eruption with cutaneous-mucosal involvement due to piroxicam. Cross-reactivity between oxicams could not be demonstrated by patch test on fixed eruption.", "affiliations": "Allergy Unit, Internal Medicine Department, Hospital La Plana, Villarreal, Castellón, Spain.", "authors": "Montoro\|J\|J\|;Díaz\|M\|M\|;Genís\|C\|C\|;Lozano\|A\|A\|;Bertomeu\|F\|F\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D000077239:Meloxicam; C032801:tenoxicam", "country": "Singapore", "delete": false, "doi": "10.1016/s0301-0546(03)79165-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0301-0546", "issue": "31(1)", "journal": "Allergologia et immunopathologia", "keywords": null, "medline_ta": "Allergol Immunopathol (Madr)", "mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001528:Behcet Syndrome; D002081:Buttocks; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D006119:Groin; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D019226:Oral Ulcer; D010328:Patch Tests; D010409:Penile Diseases; D010894:Piroxicam; D012883:Skin Ulcer; D013843:Thiazines; D013844:Thiazoles", "nlm_unique_id": "0370073", "other_id": null, "pages": "53-5", "pmc": null, "pmid": "12573211", "pubdate": "2003", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Non-pigmenting cutaneous-mucosal fixed drug eruption due to piroxicam.", "title_normalized": "non pigmenting cutaneous mucosal fixed drug eruption due to piroxicam" }	[ { "companynumb": "ES-PFIZER INC-2021485200", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "018147", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHONDROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FELDENE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCLE SPASMS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SASULEN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "018147", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "DISPERSIBLE TABLET", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHONDROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FELDENE FLASH" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fixed eruption", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MONTORO, J.. NON?PIGMENTING CUTANEOUS?MUCOSAL FIXED DRUG ERUPTION DUE TO PIROXICAM. ALLERGOLOGIA ET IMMUNOPATHOLOGIA. 2003?31 (1):53?55", "literaturereference_normalized": "non pigmenting cutaneous mucosal fixed drug eruption due to piroxicam", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210517", "receivedate": "20210517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19265419, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]
{ "abstract": "Objective Heart failure is currently the most serious complication of muscular dystrophy. The transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. In damaged myocytes or cardiomyocytes, TRPV2 translocates to the cytoplasmic membrane and enhances Ca influx, triggering cell damage. Evidence suggests that the inhibition of TRPV2 may be a new therapeutic target in heart failure. We found that tranilast, which is widely used as an anti-allergic drug, inhibits TRPV2. A pilot study was conducted to assess the safety and efficacy of tranilast in muscular dystrophy patients with cardiomyopathy. Methods After obtaining informed consent, two muscular dystrophy patients with advanced heart failure took tranilast (300 mg/day) for three months. Blood tests, echocardiography, electrocardiography (ECG), Holter ECG, analyses of the TRPV2 expression in peripheral mononuclear cells, and circulating micro ribonucleic acid profiling were performed to assess the safety and efficacy of tranilast. Results The brain natriuretic peptide levels decreased after treatment. The expression of TRPV2 on the cytoplasmic membrane of peripheral mononuclear cells was enhanced before treatment and was decreased after treatment. Some heart-related micro ribonucleic acids (miR-208a-5p, miR-223-3p) were elevated and then decreased after treatment. Some adverse events, including the potentiation of warfarin, the worsening of renal dysfunction, an increased heart rate and premature ventricular contractions, were observed. Conclusion Tranilast can inhibit TRPV2 and can be effective for treating heart failure, even in patients with muscular dystrophy. Although careful attention is needed, the inhibition of TRPV2 can be a new treatment target for cardiomyopathy. A multi-center trial is planned.", "affiliations": "Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Japan.;Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.", "authors": "Matsumura\|Tsuyoshi\|T\|;Matsui\|Misa\|M\|;Iwata\|Yuko\|Y\|;Asakura\|Masanori\|M\|;Saito\|Toshio\|T\|;Fujimura\|Harutoshi\|H\|;Sakoda\|Saburo\|S\|", "chemical_list": "D002121:Calcium Channel Blockers; D062367:ortho-Aminobenzoates; C012293:tranilast", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8651-16", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2909338410.2169/internalmedicine.8651-16Original ArticleA Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy Matsumura Tsuyoshi 1Matsui Misa 1Iwata Yuko 2Asakura Masanori 3Saito Toshio 1Fujimura Harutoshi 1Sakoda Saburo 1\n1 Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan\n2 Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Japan\n3 Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, JapanCorrespondence to Dr.　Tsuyoshi Matsumura, tmatsumura-toneyama@umin.org\n\n1 11 2017 1 2 2018 57 3 311 318 3 12 2016 6 6 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Objective \nHeart failure is currently the most serious complication of muscular dystrophy. The transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. In damaged myocytes or cardiomyocytes, TRPV2 translocates to the cytoplasmic membrane and enhances Ca influx, triggering cell damage. Evidence suggests that the inhibition of TRPV2 may be a new therapeutic target in heart failure. We found that tranilast, which is widely used as an anti-allergic drug, inhibits TRPV2. A pilot study was conducted to assess the safety and efficacy of tranilast in muscular dystrophy patients with cardiomyopathy. \n\nMethods \nAfter obtaining informed consent, two muscular dystrophy patients with advanced heart failure took tranilast (300 mg/day) for three months. Blood tests, echocardiography, electrocardiography (ECG), Holter ECG, analyses of the TRPV2 expression in peripheral mononuclear cells, and circulating micro ribonucleic acid profiling were performed to assess the safety and efficacy of tranilast. \n\nResults \nThe brain natriuretic peptide levels decreased after treatment. The expression of TRPV2 on the cytoplasmic membrane of peripheral mononuclear cells was enhanced before treatment and was decreased after treatment. Some heart-related micro ribonucleic acids (miR-208a-5p, miR-223-3p) were elevated and then decreased after treatment. Some adverse events, including the potentiation of warfarin, the worsening of renal dysfunction, an increased heart rate and premature ventricular contractions, were observed. \n\nConclusion \nTranilast can inhibit TRPV2 and can be effective for treating heart failure, even in patients with muscular dystrophy. Although careful attention is needed, the inhibition of TRPV2 can be a new treatment target for cardiomyopathy. A multi-center trial is planned. \n\ncardiomyopathycardioprotective therapymuscular dystrophytranilasttransient receptor potential cation channelsubfamily Vmember 2 (TRPV2)\n==== Body\nIntroduction\nThe life expectancy of patients with muscular dystrophy, including those with Duchenne muscular dystrophy (DMD), has been dramatically improved by mechanical ventilation. Now, heart failure is the most important complication in muscular dystrophy (1). Although cardioprotective agents such as angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) and beta-blockers have shown some effects (2), the cardiac function does not fully recover under treatment with these drugs, and the situation remains unsatisfactory for both patients and physicians. Since it is difficult for muscular dystrophy patients to undergo surgical interventions such as ventriculoplasty, artificial heart implantation, and cardiac transplantation, the development of efficient pharmacological treatments is an urgent task.\n\nThe transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. It is normally localized in the intracellular membrane compartments but translocates to the cytoplasmic membrane in damaged myocytes or cardiomyocytes and enhances the influx of Ca, which triggers the cell damage process (3). The overexpression of TRPV2 on the cytoplasmic membrane is observed in the cardiac and skeletal muscle of mdx mice and BIO 14.6 hamsters, animal models of muscular dystrophy that contain mutations in dystrophin and δ-sarcoglycan, respectively (4). The overexpression of TRPV2 at the sarcolemma was also observed in the skeletal muscle and cardiomyocytes of muscular dystrophy patients (4, 5) and cardiomyocytes of dilated cardiomyopathy (DCM) patients (5). Transgenic mice with the cardiac-specific overexpression of TRPV2 develop DCM (4).\n\nThe inhibition of TRPV2 using mutant TRPV2 and Ca-handling agents blocked the abnormal intracellular Ca influx and ameliorated the muscle pathology and motor function in mdx mice and BIO14.6 hamsters (6-8). In addition, the overexpression of the NT domain of TRPV2 blocked the plasma membrane accumulation of TRPV2 and improved cardiomyopathy in various animal models of DCM (4C30 mice, DOX-induced DCM mice, J2N-k hamsters) (5). We developed a high-throughput screening method and detected some compounds showing the inhibition of TRPV2. Tranilast, which is already approved as an anti-allergic drug, is one such drug and was effective in BIO14.6 hamsters and J2N-k hamsters (5, 6).\n\nThese facts suggest that tranilast could be useful in muscular dystrophy patients. Thus, we performed a pilot study in which tranilast was used to treat two muscular dystrophy patients with advanced cardiomyopathy. In both patients, the serum level of brain natriuretic peptide (BNP) decreased after the initiation of tranilast therapy.\n\nMaterials and Methods\nThe study protocol\nThe aim of this pilot study was to evaluate the safety and efficacy of tranilast in the treatment of heart failure in patients with muscular dystrophy. In addition, since this was the first study of the use of tranilast in the treatment of heart failure in humans, we also gathered data to assess the pharmacological mechanisms. The effects of tranilast on cardiomyopathy in animal models were dose-dependent. Since there had been some clinical trials using tranilast (600 mg/day) (9-11), a dose escalation study, in which tranilast was started at a dose of 300 mg/day and gradually titrated up to 600 mg/day (unless there were adverse events), was initially considered. However, the pharmaceutical company recommended that dose escalation be avoided, since they had seen increased adverse effects, such as urocystitis-like symptoms (1-5%) and hepatic dysfunction (11-23%), at higher doses (9-11). In addition, the ethics review board prescribed the use of the approved dose (300 mg/day). Consequently, the study was designed as an open single-arm study of tranilast (300 mg/day) for three months.\n\nThe subjects were muscular dystrophy patients who were ＞20 years of age with severe cardiac dysfunction [left ventricular dimension in diastole (LVDd)＞50 mm, FS＜20%]. Patients with severe hepatic dysfunction, renal dysfunction, eosinophilia, leucopenia, or thrombocytopenia were excluded since urocystitis-like symptoms, hepatic dysfunction/jaundice, renal dysfunction, leucopenia, and thrombocythemia are listed as clinically significant adverse reactions (unknown frequency) in the interview form for tranilast.\n\nAfter providing their informed consent, the participants took tranilast (300 mg/day) for three months. In principle, the doses of drugs that affect the cardiac function, such as ACEIs/ARBs, beta blockers, diuretics, digitalis, inotropic agents, and antiarrhythmic agents, were fixed during the study period. However, the attending physicians could optimize them when they recognized the need based on the patient's physical condition and/or laboratory data. The dose of tranilast was also fixed. However, the attending physicians could also adjust it when they considered that adverse events had occurred in association with the administration of tranilast and that the adjustment of the tranilast dose was necessary.\n\nClinical assessments were performed before and at one and three months after the initiation of tranilast (Fig. 1). Even when tranilast was stopped, the clinical assessments were continued on the same schedule.\n\nFigure 1. The protocol of this pilot study.\n\nTo assess the effects, cardiac functional indices, including echocardiographic parameters (LVDd, FS) and natriuretic peptide levels (human atrial natriuretic peptide: hANP, BNP), and cardiomyocyte damage indices, such as cardiac troponin T (cTnT) and creatine kinase isoform (CK-MB), were examined. The plasma transforming growth factor-beta 1 (TGF-β1) levels were evaluated, the TRPV2 expression in peripheral mononuclear cells (MNCs) was analyzed, and circulating micro ribonucleic acid (miRNA) profiling was performed to assess the pharmacological mechanisms. For the analysis of the TRPV2 expression in MNCs and miRNA profiling, control samples were obtained from four healthy adult volunteers. The participants understood that they were being included as a control in this study and provided their informed consent.\n\nCardiac events (deterioration of heart failure requiring intravenous inotropic, antiarrhythmic, and/or diuretic agents, cardiac death, total death), subjective symptoms, and vital signs (blood pressure, pulse rate, percutaneous oxygen saturation) were monitored. The New York Heart Association (NYHA) classification was not suitable for these patients because they were bedridden and could not perform daily activities.\n\nTo assess the safety, Holter electrocardiography (ECG) [mean heart rate, total number of premature ventricular contractions (PVCs)], blood tests [WBCs, eosinophils (Eo), platelets (Plt)], blood chemistry [cystatin C (CysC), creatinine (Crn), blood urea nitrogen (BUN), uric acid (UA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), lactate dehydrogenase (LDH), total bilirubin (T.Bil), C-reactive protein (CRP), Na, K, Cl], the international normalized ratio (INR) of prothrombin time, and a urinalysis (urinary protein, urinary sugar, occult blood) were also performed.\n\nThe primary endpoints of this study were LVDd and FS. The secondary endpoints were BNP, cTnT, and cardiac events. In unstable patients, additional assessments were performed to see the detailed changes. With regard to treatment after the study, the plan was to stop tranilast and then provide the best available care. However, if tranilast seemed effective, the participants could choose to continue treatment.\n\nThe protocol of this study was in accordance with the Declaration of Helsinki and was approved by the ethics board of National Hospital Organization Toneyama National Hospital (No. 1441). The protocols for the analysis of the TRPV2 expression in MNCs and miRNA profiling were approved by the ethics board of the National Cerebral and Cardiovascular Center (M27-080-2).\n\nThe analysis of the TRPV2 expression in MNCs\nMNCs were isolated from blood samples gathered into ethylenediaminetetraacetic acid (EDTA)-Na using Lymphoprep™ (Axis-SHIELD PoC AS, Oslo, Norway), and were then centrifuged at 800×g for 30 minutes at room temperature.\n\nFor immunostaining, we used affinity-purified polyclonal anti-TRPV2 antibodies (4, 5) which were raised by immunizing rabbits with a glutathione S-transferase (GST) fusion protein containing aa634-756 of mouse TRPV2 protein. Isolated MNCs immobilized on glass slides were fixed with 4% paraformaldehyde for 15 minutes at room temperature, permeabilized with 0.1% Triton™ X-100 (Axis-SHIELD PoC AS), incubated with the antibody (1 : 100 dilution) overnight at 4℃, and then incubated for 30 minutes at room temperature with Alexa Fluor 488 goat anti-rabbit IgG (H+L) (1 : 500 dilution) (Invitrogen, Carlsbad, USA).\n\nImages of MNCs stained with TRPV2 antibodies were analyzed by investigators (who were blinded to the samples), by confocal laser scanning microscopy (FLUOVIEWTM FV1000, Olympus, Tokyo, Japan) mounted on an objective lens (Olympus), using the National Institute of Health Imaging software program. The fluorescence intensity was scanned along lines selected in the center of an MNC. The fluorescence intensity corresponding to the surface region was calculated by subtracting the intensity of the intracellular region from that of the total area. To summarize the data for the membrane localization of TRPV2, the number of MNCs with a strong fluorescence signal at the cell edge (at least three times higher than the average fluorescence in the internal region) was counted (total number of MNCs analyzed: 30-100). We repeated the experiments twice using another affinity purified TRPV2 antibody (anti-human TRPV2 antibody raised by immunizing rabbits with maltose binding protein fusion protein containing aa635-729 of human TRPV2).\n\nRNA extraction and miRNA profiling\nPlasma samples were collected from EDTA-Na blood samples by centrifugation at 1,500×g and stored at -80°C. RNA was extracted from the plasma samples using the 3D-GeneⓇ RNA extraction reagent from a liquid sample kit (TORAY, Tokyo, Japan), according to the manufacturer's instructions. The extracted total RNA was labeled with the 3D-GeneⓇ miRNA labeling kit (TORAY). Labeled RNAs were hybridized onto 3D-GeneⓇ Human miRNA Oligo chips (TORAY) (12). The annotation and oligonucleotide sequences of the probes conformed to the miRBase miRNA database (http://www.mirbase.org/). After careful washing, the fluorescence signals were scanned with a 3D-GeneⓇ Scanner (TORAY) and were analyzed using the 3D-GeneⓇ Extraction software program (TORAY).\n\nThe raw data of each spot were normalized by substitution with the mean intensity of the background signal (determined by the signal intensities of all of the blank spots' and 95% confidence intervals). The measurements of spots with signal intensities that were greater than two standard deviations of the background signal intensity were considered to be valid. The relative expression level of a given miRNA was calculated by comparing the signal intensities of the valid spots throughout the microarray experiments. The normalized data were globally normalized per array, such that the median signal intensity was adjusted to 25.\n\nPatients\nTwo muscular dystrophy patients with severe cardiac dysfunction, who agreed with the aims and protocol of this study and wished to participate, were included in the present study.\n\nThe first case (Patient 1) was a 45-year-old man with Becker muscular dystrophy (BMD). He had a deletion of exons 3 and 4 in the dystrophin gene, which was detected by multiple ligation-dependent prove amplification (MLPA). He was non-ambulatory but could sit without any support. He had developed cardiac dysfunction and had started ACEI therapy 20 years previously and beta blocker therapy 11 years previously. He was resuscitated from cardiopulmonary arrest due to ventricular tachycardia (VT) and underwent the implantation of a cardioversion-defibrillation and biventricular pacing device 6 years previously. He was then admitted to our hospital due to an exacerbation of heart failure. A stable condition was barely maintained with the best available care, which included ACEI, a beta blocker, a phosphodiesterase 3 inhibitor (PDE3I), diuretics, antiarrhythmic agents, warfarin, and night-time non-invasive ventilation (NIV). However, at the beginning of this study, he still had severe cardiac dysfunction [left ventricular dilated dimension (LVDd), 65 mm; fractional shortening (FS), 4%; BNP, 144.2 pg/mL; cTnT 0.039 ng/mL].\n\nThe second case (Patient 2) was a 46-year-old man with unclassified muscular dystrophy. He was initially diagnosed with BMD based on his clinical appearance and the findings of a histological examination of a muscle biopsy specimen in another hospital over 30 years previously, but neither MLPA nor Sanger sequencing detected mutations in the dystrophin gene. He was non-ambulatory and was not able to sit alone. He developed respiratory failure and was started on NIV 19 years previously. Cardiac dysfunction was also detected, and ACEI therapy was started 5 years previously. Non-sustained VT was detected from one year previously. He was strongly advised to take a beta blocker and/or an antiarrhythmic agent but refused because he disliked being admitted to hospital and frequent hospital visits. He developed cardiopulmonary arrest due to an acute exacerbation of heart failure and was successfully resuscitated at his home three months previously and was transferred to our hospital. Although maximal therapy was given, including ACEI, PDE3I, diuretics, antiarrhythmic agents, and full-time tracheal mechanical ventilation, he presented with recurrent multi-organ infection, and still had severe cardiac dysfunction (LVDd 61 mm, FS 6%, BNP 164.3 pg/mL, cTnT 0.016 ng/mL).\n\nBoth patients understood the protocol of this study well and participated willingly; both provided their informed consent.\n\nResults\nThe clinical findings in Patient 1\nAfter the initiation of tranilast, the INR increased from 2.25 to 3.64 within one week. The dose of warfarin was adjusted from 1.5 mg/day to 1.0 mg/day according to the INR. He initially had no subjective cardiac symptoms. Although his total energy intake was not greatly changed, his meal portion increased just before starting tranilast because the number of meals supplied was reduced from five (200 Kcal×5/day) to three (350 Kcal×3/day) per day. In addition, his mother's health had deteriorated during the study period. He felt an increased pulse rate, and it was confirmed by Holter ECG (the mean heart rate increased from 75 bpm to 88 bpm at one month, and 87 bpm at three months). The PVC also increased from 2,891 beats/day to 7,712 beats/day at one month and 8,445 beats/day at three months. Nonetheless, the plasma BNP level decreased from 144.2 pg/mL to 119.7 pg/mL at one month and 99.8 pg/mL at three months. The serum UA level decreased from 8.5 mg/dL at the beginning to 4.5 mg/dL at both one and three months. No apparent changes were detected on echocardiography (LVDd, FS) or in cTnT, CysC, or the other indices. There were no other clinically relevant changes (Fig. 2A). All of the laboratory data are presented in Supplementary material 1.\n\nFigure 2. The clinical courses of both patients.\n\nThe clinical findings in Patient 2\nThe general condition of Patient 2 was serious, with recurrent multi-organ infection. Thus, there were fluctuations in various indices. Subjective symptoms, such as general fatigue were affected by his general condition, and it was difficult to evaluate the effects of tranilast. His BNP level was also unstable, but it decreased from 164.3 pg/mL to 102.6 pg/mL at one month and 64.5 pg/mL at seven weeks. Since his CysC level was elevated from 0.92 mg/L to 2.86 mg/L, it was thought that this might be an adverse effect of tranilast, and tranilast was stopped at 52 days. In addition, his water intake increased simultaneously because the BUN level was elevated (51.4 mg/dL), and dehydration was considered. The BNP then rapidly increased to 228.5 pg/mL at 66 days. After tranilast was restarted, the patient's BNP level decreased to 114.6 pg/mL at 79 days. The serum UA level was 9.8 mg/dL before treatment, 3.5 mg/dL at one month, and 5.5 mg/dL at three months. There were no apparent changes on echocardiography, Holter ECG, or cTnT (Fig. 2B). All of the laboratory data are presented in Supplementary material 2.\n\nThe analysis of the TRPV2 expression in MNCs\nIn the control samples, TRPV2 was diffusely expressed in the cytoplasm. In the samples of both patients, TRPV2 was preferentially present on the cytoplasmic membrane (Fig. 3A, arrows). After the initiation of tranilast, the ratios of MNCs expressing TRPV2 on the cytoplasmic membrane were decreased in both cases (Fig. 3A, B). A similar result was obtained by using another TRPV2 antibody.\n\nFigure 3. The analysis of the TRPV2 expression in the peripheral MNCs. A: The immunohistochemical expression of TRPV2 in the MNCs. B: The ratio of MNCs expressing TRPV2 on the cytoplasmic membrane. Open bar: controls, black bar: Patient 1, gray bar: Patient 2. pre: pre-treatment, 1mo: One month after starting tranilast, 3mo: Three months after starting tranilast\n\nThe miRNA expression profiles\nThe chipset examined over 2,000 miRNAs. However there were only three miRNAs (miR-208a-5p, miR-223-3p, miR-4443) that were expressed at a higher level in comparison to the control samples at the beginning of treatment; they decreased to the control levels at one month after the initiation of tranilast treatment, and were maintained at the same levels at three months after treatment in both patients (Fig. 4). The expression levels of miR-1-3p, miR-1-5p, miR-133a-3p, miR-133b-miRNAs that are known as muscle miRNAs (13)-were not elevated in these patients.\n\nFigure 4. The circulating miRNA profiles. Open bar: controls, black bar: Patient 1, gray bar: Patient 2. Pt1: patient 1, Pt2: patient 2, pre: pre-treatment, 1mo: One month after starting tranilast, 3mo: Three months after starting tranilast\n\nDiscussion\nHeart failure is a crucial prognostic factor in patients with muscular dystrophy, but there are various problems in the clinical assessment of the cardiac function. First, symptoms of heart failure in these patients are difficult to recognize. Their motor dysfunction is so severe that the cardiac load is extremely low. Heart failure progresses chronically and often concurrently with respiratory failure. Mechanical ventilation also greatly decreases the cardiac load. Physicians familiar with muscular dystrophy treat heart failure from the early asymptomatic stage. Consequently, few patients complain of the symptoms of heart failure, even in the advanced stage. Thus, it is difficult to assess the effects of treatment based on the subjective symptoms.\n\nSecond, there are many limitations in the evaluation of the cardiac function. Magnetic resonance imaging is impossible for many patients because of severe deformities or the need for mechanical ventilation. Echocardiography is also difficult in some patients due to narrow echo windows because of the patients' thoracic deformities. BNP frequently remains low, even in the advanced stage of heart failure (14), and 100 pg/mL is known as a critical point for the prognosis (15). A previous study of beta blocker therapy showed improvements in cardiac events, but no obvious changes were detected in the BNP levels (2). Consequently, multiple markers and serial evaluations are needed to assess the cardiac function.\n\nBoth of the patients who participated in this pilot study had terminal-stage heart failure. Their cardiac dysfunction was quite severe, despite the provision of the best available treatment. Nonetheless, the BNP levels of both patients decreased after the initiation of tranilast. Notably, in Patient 2, the BNP rapidly increased when he stopped tranilast, and it then decreased after it was restarted. Although the echocardiographic findings showed no obvious changes, these findings suggest that tranilast has beneficial effects on cardiomyopathy in muscular dystrophy patients.\n\nSeveral assessments of the pharmacological mechanism also supported the efficacy of tranilast. The first assessment was the analysis of the TRPV2 expression. Assessments of the TRPV2 expression in cardiomyocytes before and after treatment are ideal but impractical in human patients. Instead, the TRPV2 expression in peripheral MNCs was analyzed. TRPV2 was preferentially expressed on the cytoplasmic membrane of the peripheral MNCs in both patients. After starting tranilast, the ratio of MNCs expressing TRPV2 on the cytoplasmic membrane decreased to control levels. These data suggest that tranilast can actually inhibit TRPV2, even in humans.\n\nThe second assessment was the analysis of the expression of circulating miRNAs. This study showed the elevation of the miR-208a-5p, miR-223-3p, and miR-4443 expression before treatment, with decreased to control levels in both patients after the initiation of tranilast treatment. Among these miRNAs, miR-208a-5p is known to be a regulator of cardiac hypertrophy (16), and its inhibition is reported to improve heart failure (17). In addition, miR-233-3p is known as a marker of heart disease (18, 19). Although there were no changes in the cTnT level, these findings implied that tranilast can ameliorate cardiac damage. These findings not only supported the effects of tranilast, but also suggested that these assessments can be biomarkers in TRPV2 inhibition therapy.\n\nIt should be noted that the expression levels of miR-1s and miR-133s were not elevated in these patients. Although these miRNAs have been reported to be elevated in patients with muscular dystrophy (13), the present results seemed natural because both patients were advanced cases with severe muscle atrophy.\n\nWith respect to safety, several adverse events occurred during the study period. It is well known that tranilast, which is mainly metabolized by CYP2C9, has synergistic effects with warfarin. Patient 1, who took warfarin, showed an elevated INR and his dose of warfarin required adjustment. Renal dysfunction is also a known adverse effect of tranilast. Based on the interview form, Crn elevation was found in 0.004% of patients who received the approved dose and 9.5% of the patients who received a higher dose (10). In the present study, Patient 2 showed cystatin C elevation. We suspected that dehydration and recurrent infection might also have affected the renal function, and his water intake was increased, but the value remained high. Thus, there was a high possibility that tranilast impaired the renal function. Since renal dysfunction is not rare in muscular dystrophy patients with heart failure (20), it can be a limiting factor. An increased heart rate and PVCs were observed in Patient 1. Tranilast is not known to cause such events. An increase in the food portions and/or mental stress might have been related to the patient's increased heart rate; however, an adverse effect of tranilast could not be ruled out. Although tranilast has been widely used in the general population, careful attention is needed when it is used in the treatment of patients with severe heart failure.\n\nThe results obtained from this pilot study suggest that the inhibition of TRPV2 might become a new therapeutic target for heart failure and myopathy. New options for the treatment of heart failure are of great clinical importance. We are planning multi-center clinical trials to clarify the safety and efficacy of tranilast.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis study was partly supported by a Health and Labour Sciences Research Grant for Comprehensive Research on Persons with Disabilities from Japan Agency for Medical Research and Development (15Adk0310043h0002) and an Intramural Research Grant (25-5, 26-6) for Neurological and Psychiatry Disorders of NCNP. The funders had no roles in the study design, data collection and analyses, decision to publish, or the preparation of the manuscript.\n\nSupplementary Materials\nSupplementary table 1 Laboratory data of Patient 1\n\nClick here for additional data file.\n\n Supplementary table 2 Laboratory data of Patient 2\n\nClick here for additional data file.\n\n Acknowledgement\nThe authors are grateful to Drs. Ryu Nagata and Hideki Ohta of the Japan Agency for Medical Research and Development for their kind advice on the circulating miRNA and metabolome analyses.\n==== Refs\n1. Matsumura T , Saito T , Fujimura H , Shinno S , Sakoda S \nA longitudinal cause-of-death analysis of patients with Duchenne muscular dystrophy . Rinsho Shinkeigaku \n51 : 743 -750 , 2011 (in Japanese, Abstract in English).22019865 \n2. Matsumura T , Tamura T , Kuru S , Kikuchi Y , Kawai M \nCarvedilol can prevent cardiac events in Duchenne muscular dystrophy . Intern Med \n49 : 1357 -1363 , 2010 .20647648 \n3. Kanzaki M , Zhang YQ , Mashima H , Shibata H , Kojima I \nTranslocation of a calcium-permeable cation channel induced by insulin-like growth factor-1 . Nat Cell Biol \n1 : 165 -170 , 1999 .10559903 \n4. Iwata Y , Katanosaka Y , Arai Y , Komamura K , Miyatake K , Shigekawa M \nA novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel . J Cell Biol \n161 : 957 -967 , 2003 .12796481 \n5. Iwata Y , Ohtake H , Suzuki O , Matsuda J , Komamura K , Wakabayashi S \nBlockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy . Cardiovasc Res \n99 : 760 -768 , 2013 .23786999 \n6. Iwata Y , Katanosaka Y , Shijun Z , et al \nProtective effects of Ca2+ handling drugs against abnormal Ca2+ homeostasis and cell damage in myopathic skeletal muscle cells . Biochem Pharmacol \n70 : 740 -751 , 2005 .16009351 \n7. Iwata Y , Katanosaka Y , Arai Y , Shigekawa M , Wakabayashi S \nDominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models . Hum Mol Genet \n18 : 824 -834 , 2009 .19050039 \n8. Zanou N , Iwata Y , Schakman O , Lebacq J , Wakabayashi S , Gailly P \nEssential role of TRPV2 ion channel in the sensitivity of dystrophic muscle to eccentric contractions . FEBS Lett \n583 : 3600 -3604 , 2009 .19840792 \n9. Kato K , Tamai H , Hayakawa H , et al \nClinical evaluation of tranilast on restenosis after percutaneous transluminal coronary angiopathy (PTCA) -a double-blind placebo-controlled comparative study- . Rinshoiyaku \n12 : 65 -85 , 1996 (in Japanese, Abstract in English).\n10. Itagane H , Haji K , Kodama K , et al \nEffects of tranilast on restenosis after percutaneous transluminal coronary angiopathy -a multi center phase III open trial- . Shinnyaku to Rinsho \n45 : 267 -280 , 1996 (in Japanese, Abstract in English).\n11. Takekoshi N , Kanemitsu S , Kitayama M , et al \nClinical evaluation of tranilast in the prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) -a phase III multicenter open trial- . Kiso to Rinsho \n30 : 593 -609 , 1996 (in Japanese, Abstract in English).\n12. Nagino K , Nomura O , Takii Y , et al \nUltrasensitive DNA chip: gene expression profile analysis without RNA amplification . J Biochem \n139 : 697 -703 , 2006 .16672270 \n13. Cacchiarelli D , Legnini I , Martone J , et al \nmiRNAs as serum biomarkers for Duchenne muscular dystrophy . EMBO Mol Med \n3 : 258 -265 , 2011 .21425469 \n14. Demachi J , Kagaya Y , Watanabe J , et al \nCharacteristics of the increase in plasma brain natriuretic peptide level in left ventricular systolic dysfunction, associated with muscular dystrophy in comparison with idopathic dilated cardiomyopathy . Neurmuscul Disord \n14 : 732 -739 , 2004 .\n15. Adachi K , Kawai H , Kimura C , et al \nEstimation of the prognosis of patients with Duchenne muscular dystrophy and cardiac failure on their plasma level of natriuretic peptide . Shinkeinaika 1998 \n49 : 532 -536 , 1998 (in Japanese, Abstract in English).\n16. Callis TE , Pandya K , Seok HY , et al \nMicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice . J Clin Invest \n119 : 2772 -2786 , 2009 .19726871 \n17. Montgomery RL , Hullinger TG , Semus HM , et al \nTherapeutic inhibition of miR-208a improves cardiac function and survival during heart failure . Circulation \n124 : 1537 -1547 , 2011 .21900086 \n18. Dickinson BA , Semus HM , Montgomery RL , et al \nPlasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure . Eur J Heart Fail \n15 : 650 -659 , 2013 .23388090 \n19. Barsanti C , Trivella MG , D'Aurizio R , et al \nDifferential regulation of microRNAs in end-stage failing hearts is associated with left ventricular assist device unloading . Biomed Res Int \n2015 (Epub ahead of print).\n20. Matsumura T , Saito T , Fujimura H , Sakoda S \nRenal dysfunction is a frequent complication in patients with advanced stage of Duchenne muscular dystrophy . Rinsho Shinkeigaku \n52 : 211 -217 , 2012 (in Japanese, Abstract in English).22531652\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(3)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "cardiomyopathy; cardioprotective therapy; member 2 (TRPV2); muscular dystrophy; subfamily V; tranilast; transient receptor potential cation channel", "medline_ta": "Intern Med", "mesh_terms": "D002121:Calcium Channel Blockers; D004334:Drug Administration Schedule; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D009136:Muscular Dystrophies; D010865:Pilot Projects; D062367:ortho-Aminobenzoates", "nlm_unique_id": "9204241", "other_id": null, "pages": "311-318", "pmc": null, "pmid": "29093384", "pubdate": "2018-02-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21900086;16672270;21425469;25710008;12796481;19050039;22019865;19726871;23388090;20647648;15482958;19840792;16009351;10559903;22531652;23786999", "title": "A Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy.", "title_normalized": "a pilot study of tranilast for cardiomyopathy of muscular dystrophy" }	[ { "companynumb": "PHHY2018JP068865", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75048", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC DYSFUNCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiopulmonary failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ventricular tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUMURA T, MATSUI M, IWATA Y, ASAKURA M, SAITO T, FUJIMURA H ET AL.. 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A PILOT STUDY OF TRANILAST FOR CARDIOMYOPATHY OF MUSCULAR DYSTROPHY. INTERN MED. 2018?57(3):311?318", "literaturereference_normalized": "a pilot study of tranilast for cardiomyopathy of muscular dystrophy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180828", "receivedate": "20180817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15287049, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-TEVA-2018-JP-945725", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRANILAST" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; FOR 3 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BECKER^S MUSCULAR DYSTROPHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRANILAST" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ventricular extrasystoles", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUMURA T, MATSUI M, IWATA Y, ASAKURA M, SAITO T, FUJIMURA H, ET AL. A PILOT STUDY OF TRANILAST FOR CARDIOMYOPATHY OF MUSCULAR DYSTROPHY. INTERN?MED 2018?57(3):311?318.", "literaturereference_normalized": "a pilot study of tranilast for cardiomyopathy of muscular dystrophy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180820", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15293542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Düzova A, Gülhan B, Topaloğlu R, Özaltın F, Cengiz AB, Yetimakman AF, Doğru D, Güçer Ş, Beşbaş N. BK virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with Schimke immune-osseous-dysplasia. Turk J Pediatr 2019; 61: 111-116. Patients with juvenile onset Schimke immune-osseous-dysplasia (SIOD) have less severe symptoms and can survive in the second and third decade of life. We present an 18 year-old adolescent with juvenile onset SIOD who was diagnosed after renal transplantation and developed BK virus associated nephropathy (BKVAN) and severe pneumonia during follow-up. The patient developed nephrotic syndrome, unresponsive to immunosuppressives, at the age of 8 years. He had a history of meningitis, short stature, microcephaly, prominent ears, and bilateral cryptorchidism. A renal transplantation was performed at the age of 15 years. During follow-up, he suffered from leucopenia, urinary tract infections, herpes labialis, and candida esophagitis. Sanger sequencing of SMARCAL1 revealed a missense mutation on exon 11 (R586W). A renal biopsy performed after a sharp increase in serum creatinine (without significant viremia) revealed BKVAN which responded to sirolimus monotherapy and cidofovir. Three months later, he suffered from productive cough and dyspnea with diffuse ground glass pulmonary infiltrates. His clinical situation deteriorated and non-invasive mechanical ventilation was started. Cidofovir (2 mg/kg) was re-started weekly for a possible BKV pneumonia with intravenous immunoglobulin. After 5 doses of cidofovir and intense antibiotic regime, his dyspnea resolved with stable graft functions. In our case; BKVAN, which developed without significant viremia, and possibly associated pneumonia were treated successfully with cidofovir and sirolimus monotherapy.", "affiliations": "Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Intensive Care, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Pulmonary Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatric and Perinatal Pathology Research, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.", "authors": "Düzova\|Ali\|A\|;Gülhan\|Bora\|B\|;Topaloğlu\|Rezan\|R\|;Özaltın\|Fatih\|F\|;Cengiz\|Ali Bülent\|AB\|;Yetimakman\|Ayşe Filiz\|AF\|;Doğru\|Deniz\|D\|;Güçer\|Şafak\|Ş\|;Beşbaş\|Nesrin\|N\|", "chemical_list": "C412482:SMARCAL1 protein, human; D004265:DNA Helicases", "country": "Turkey", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-4301", "issue": "61(1)", "journal": "The Turkish journal of pediatrics", "keywords": "BK virus associated nephropathy; Schimke immuneosseous- dysplasia; kidney transplant; pneumonia; sirolimus", "medline_ta": "Turk J Pediatr", "mesh_terms": "D000293:Adolescent; D001161:Arteriosclerosis; D001739:BK Virus; D004265:DNA Helicases; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias; D011024:Pneumonia, Viral; D027601:Polyomavirus Infections; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism; D066027:Transplant Recipients", "nlm_unique_id": "0417505", "other_id": null, "pages": "111-116", "pmc": null, "pmid": "31559731", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": null, "title": "BK virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with Schimke immuneosseous- dysplasia.", "title_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia" }	[ { "companynumb": "TR-BAUSCH-BL-2019-062319", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40070", 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN A" } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, CENGIZ A, YETIMAKMAN A, DOGRU D, GUCER S, BESBAS N. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. THE TURKISH JOURNAL OF PEDIATRICS. 2019?61(1):111-116. DOI:10.24953/TURKJPED.2019.01.018", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191202", "receivedate": "20191202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17100204, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019TR040591", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE INCREASED", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "65379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A ET AL.. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA.. TURKISH JOURNAL OF PEDIATRICS. 2019?61(1):111-6", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191121", "receivedate": "20191121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17060417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-ACCORD-162396", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PREDNISOLONE DOSAGE WAS INCREASED", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA L, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURKISH JOURNAL OF PEDIATRICS. 2019?61(1):111-116.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191130", "receivedate": "20191130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17094769, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-TEVA-2019-TR-1146553", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viral test positive", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral herpes", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cytomegalovirus test positive", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA L, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A, ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURK-J-PEDIATR 2019?61(1):111-116.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200106", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17118180, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "TR-PBT-000012", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "05203", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": 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"drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "05203", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN (CYCLOSPORIN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL CANDIDIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": "3", "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, CENGIZ AB, YETIMAKMAN AF ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS- DYSPLASIA. TURK J PEDIATR. 2019?61(1):111-116. DOI: 10.24953/TURKJPED.2019.01.018.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191014", "receivedate": "20191014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16913433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-PBT-000041", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "829160000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "3", "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oral herpes", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mouth ulceration", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kidney transplant rejection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, CENGIZ AB, YETIMAKMAN AF, ET. AL BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURKISH JOURNAL OF PEDIATRICS. 2019 JAN 1?61(1).", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200513", "receivedate": "20200513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17779233, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]
{ "abstract": "OBJECTIVE\nAdamantinomas are primary, low-grade malignant tumors of the bone that have metastatic potential to the lungs, lymph nodes, and other regions. The rarity of this disease and its nonspecific symptoms complicate diagnosis.\n\n\nMETHODS\nRecords for 20 patients who underwent treatment for adamantinoma from 1975 to 2018 were reviewed for demographic, clinical, and pathological data, treatment details, postoperative complications, and outcomes.\n\n\nRESULTS\nPatients presented at a median age of 22 years (1-79 years): 14 patients had a localized primary tumor, three presented with local recurrence, and three with metastatic disease. Median tumor size was 5.7 cm (0.5-15.5 cm). Wide excision was performed primarily in 15 cases; the remaining five patients underwent intralesional curettage. At a median follow-up of 7.3 years, 14 patients had no evidence of disease; two patients were alive with disease, and four patients died from the disease. Local recurrence and distant metastasis occurred at a median of 11.4 years (6 month-19 years) and 15.8 years (4 month-23 years) after diagnosis.\n\n\nCONCLUSIONS\nAdequate histopathological diagnosis is crucial to avoid misdiagnosis of this rare tumor. Local and distant recuAbs_Para_meprrence can occur more than 20 years after the initial diagnosis. Life-long follow-up with clinical examination and imaging is required.", "affiliations": "Sloan Kettering Institute, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.", "authors": "Schwarzkopf\|Eugenia\|E\|http://orcid.org/0000-0002-0305-5686;Tavarez\|Yoely\|Y\|;Healey\|John H\|JH\|http://orcid.org/0000-0002-0802-1186;Hameed\|Meera\|M\|;Prince\|Daniel E\|DE\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/jso.25950", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-4790", "issue": "122(2)", "journal": "Journal of surgical oncology", "keywords": "adamantinoma; bone-tumor; low-grade; osteofibrous dysplasia", "medline_ta": "J Surg Oncol", "mesh_terms": "D050398:Adamantinoma; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011183:Postoperative Complications; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "0222643", "other_id": null, "pages": "273-282", "pmc": null, "pmid": "32334443", "pubdate": "2020-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1391818;18279517;2020866;3201280;30332521;1112840;16550582;27745864;21983933;3312206;29770232;2743266;8425352;18521211;9808442;16636523;7929496;19048403;27630780;2017924;3514033;17375547;3952546;10954102;2161603;7511328;6181697;6207973;16906392;12679847;17939469;28249983;7567680;31021853", "title": "Adamantinomatous tumors: Long-term follow-up study of 20 patients treated at a single institution.", "title_normalized": "adamantinomatous tumors long term follow up study of 20 patients treated at a single institution" }	[ { "companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2020-00252", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, 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{ "abstract": "Cocoon abdomen is a rare condition in which abdominal structures are surrounded by thick encapsulating peritoneum resulting in dense adhesions. Liver transplant is a high risk surgery with an already increased risk of massive blood loss due to the pre-existing coagulopathy and portal hypertension. Presence of cocoon abdomen with severe dense adhesions can either lead to difficult hepatectomy with massive intra-operative blood loss or failure to proceed with the surgery. This becomes even more important in live donor liver transplantation where it may not be possible to abandon the surgery once the donor liver resection is started. Thus keeping a high suspicion of cocoon abdomen in patients with previous history of kochs abdomen and on long term beta blocker therapy is of utmost importance and this can decrease the morbidity and mortality associated with this condition. A 41 year old male known case of chronic liver disease was posted for live donor liver transplantation. After opening the abdomen thick dense adhesions were found around the intestines and the liver. Due to the dense adhesions surgical team was in dilemma whether to proceed further for the surgery or not. Intra-operatively patient had a blood loss of 12.5 litre. Despite massive transfusion the postoperative course went uneventful and the patient was extubated on 2nd post-operative day. He was shifted out of Intensive care unit on the 6th post-operative day. Cocoon abdomen should be suspected in a chronic liver disease patient with previous history of tuberculosis or on long term beta blocker therapy. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly shows that such types of patients can be taken up for the live donor liver transplantation surgery with a precaution to start donor hepatectomy only after surgeon has assessed the difficulty status of recipient hepatectomy.", "affiliations": "Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of HPB and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India.", "authors": "Garg\|Neha\|N\|;Sindwani\|Gaurav\|G\|;Arora\|Mahesh Kumar\|MK\|;Pamecha\|Vinyendra\|V\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/sja.SJA_655_18", "fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-13-7510.4103/sja.SJA_655_18Case ReportLiving donor liver transplantation in a patient with cocoon abdomen – Anesthesia concerns! Garg Neha Sindwani Gaurav Arora Mahesh Kumar Pamecha Vinyendra 1Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India1 Department of HPB and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, IndiaAddress for correspondence: Dr. Gaurav Sindwani, Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi - 110 070, India. E-mail: drsindwani25@gmail.comJan-Mar 2019 13 1 75 77 Copyright: © 2018 Saudi Journal of Anesthesia2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Cocoon abdomen is a rare condition in which abdominal structures are surrounded by thick encapsulating peritoneum resulting in dense adhesions. Liver transplant is a high risk surgery with an already increased risk of massive blood loss due to the pre-existing coagulopathy and portal hypertension. Presence of cocoon abdomen with severe dense adhesions can either lead to difficult hepatectomy with massive intra-operative blood loss or failure to proceed with the surgery. This becomes even more important in live donor liver transplantation where it may not be possible to abandon the surgery once the donor liver resection is started. Thus keeping a high suspicion of cocoon abdomen in patients with previous history of kochs abdomen and on long term beta blocker therapy is of utmost importance and this can decrease the morbidity and mortality associated with this condition. A 41 year old male known case of chronic liver disease was posted for live donor liver transplantation. After opening the abdomen thick dense adhesions were found around the intestines and the liver. Due to the dense adhesions surgical team was in dilemma whether to proceed further for the surgery or not. Intra-operatively patient had a blood loss of 12.5 litre. Despite massive transfusion the postoperative course went uneventful and the patient was extubated on 2nd post-operative day. He was shifted out of Intensive care unit on the 6th post-operative day. Cocoon abdomen should be suspected in a chronic liver disease patient with previous history of tuberculosis or on long term beta blocker therapy. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly shows that such types of patients can be taken up for the live donor liver transplantation surgery with a precaution to start donor hepatectomy only after surgeon has assessed the difficulty status of recipient hepatectomy.\n\nCocoon abdomenliving donorliver transplantation\n==== Body\nIntroduction\nCocoon abdomen is a rare condition characterized by thick peritoneum encapsulating the abdominal structures with adhesions.[1] It is also called as sclerosing encapsulating peritonitis. In most cases, it is diagnosed incidentally on laparotomy.[2] It usually presents clinically as acute or subacute small bowel obstruction.[3] Liver transplantation is a major surgery which usually requires multiple transfusions. There are various risk factors predisposing to blood loss such as history of previous abdominal surgery, presence of coagulopathy, presence of multiple collaterals, massive fluid resuscitation, hypothermia, and hypocalcemia. The presence of cocoon abdomen results in multiple adhesions. Moreover, with an increase in the chronicity of liver disease, the number of collaterals increases, which further infiltrates the adhesions present in cocoon abdomen. This causes further increase in blood loss in an already challenging surgery like liver transplantation and can pose a great challenge for an anesthetist. As per our literature search, the presence of cocoon abdomen also involving liver hilum leading to massive transfusion in a patient undergoing liver transplantation has not been reported. Hence, we present a case of a 41-year-old male patient with history of pulmonary tuberculosis for liver transplantation, incidentally diagnosed to have cocoon abdomen intraoperatively, leading to massive transfusion and dilemma whether to proceed further for the surgery.\n\nCase\nA 41-year-old male, weighing 76 kg, diagnosed with ethanol-related chronic liver disease with treated pulmonary tuberculosis was posted for living donor liver transplantation. He had history of pulmonary tuberculosis 6 months ago. The patient also had a history of ascites for which he was on tablet furosemide 80 mg/day and tablet metoprolol 25 mg. He had an Model for End stage Liver Disease (MELD) score of 30. Chest X-ray showed mild pleural effusion of the right side. Bubble contrast ECHO showed moderate shunting with room air PAO2 of 61 mmHg. On the day of the surgery, the patient was taken inside the operation theater. All standard American Society of Anaesthesiologists (ASA) monitors were attached. An 18-G intravenous cannula was secured in the left upper limb. General anesthesia was induced with inj. propofol 100 mg i.v., inj. fentanyl 100 μg i.v., and inj. rocuronium 100 mg i.v. Trachea was intubated with 8.5 Endotracheal Tube (ETT) and the patient was put on mechanical ventilation. Ultrasound-guided one 8.5-F four-lumen central line and one 9-F triple-lumen advanced vascular access sheath were secured in the right internal jugular vein. Two 20-G arterial cannula were secured, one each in radial artery. Fluid warmer, forced air warmer, and heating mattress were used to maintain normothermia in the patient. Anesthesia was maintained with oxygen and air (50:50), isoflurane, 1.5 μg/kg/h fentanyl infusion, and 0.5 mg/kg/hatracurium infusion. After opening the abdomen, dense adhesions with encapsulation of liver and bowel were found [Figure 1]. Along with this, multiple collaterals in hepatoduodenal ligament, perigastric region, pericholedochal, peri-gall bladder, and perimesentric were also present. This resulted in blood loss of 12.5 L in the dissection phase which was replaced with transfusion of 35 units of Packed Red Blood Cells (PRBCs), 15 units of cryoprecipitate, 15 units of Fresh Frozen Plasma (FFP), and 3 single-donor platelet concentrate; 24 L of plasmalyte and 2.25 L of albumin were also given. Noradrenaline and vasopressin were titrated intraoperatively to maintain a minimum mean arterial pressure of 60 mmHg. Warm ischemia time was 29 min, and the cold ischemia time was 1 h 36 min. The rest of the surgery went uneventful with mild post-reperfusion syndrome which was managed with 400 μg bolus of phenylephrine. The patient was shifted to the intensive care unit for elective mechanical ventilation with vasopressor support of noradrenaline 8 μg/min and vasopressin 1 unit/h. The liver functions started improving in the immediate postoperative period indicated by decreasing lactate levels, prothrombin time, International Normalized Ratio (INR), bilirubin, Aspartate Transaminase (AST), and (ALT) Alanine transaminases levels with good portal vein flow and hepatic artery flow on Doppler. The patient was successfully extubated on the second postoperative day despite massive transfusion and shifted out of the intensive care unit on the sixth postoperative day.\n\nFigure 1 Cocoon abdomen involving whole of the intestines with the liver graft in situ\n\n\nDiscussion\nCocoon abdomen is a rare condition in which thick fibrotic peritoneum covers the bowel along with adhesions. It is mostly found in females. It is of two types, primary and secondary. Primary is more common and is found in young females, proposed to arise from retrograde menstruation or primary transvaginal peritonitis. Secondary is due to B adrenergic blockers, abdominal tuberculosis, chronic ambulatory peritoneal dialysis, and liver cirrhosis after peritoneal venous shunt.[45]\n\nPreoperative diagnosis is difficult. Clinically, patients present with recurrent intestinal obstruction. Radiologic findings may help in suspected cases. Plain radiograph and oral contrast show a compact mass of bowel with delayed or absent passage of contrast. Ultrasound shows a tightly bound mass of bowel surrounded by a rim of echo poor tissue. Similarly, computed tomography scan can show a circumscribed cluster of small bowel loops.[67] Unfortunately, our patient did not have any of these findings preoperatively which could have lead to preoperative diagnosis of Sclerosing Encapsulating Peritonitis (SEP).\n\nOur patient had ethanol-related chronic liver disease with a previously diagnosed pulmonary tuberculosis which may have been attributed to SEP. The mechanism by which pulmonary tuberculosis can spread to abdomen includes ingestion of infected sputum, through lymphatic channels or through blood vessels. Thus, a high degree of suspicion for abdominal tuberculosis must be kept in mind for patients with pulmonary kochs presenting for liver transplant, and attempts for appropriate diagnosis for cocoon abdomen must be made preoperatively.\n\nOther etiology which might have caused SEP in our patient was the long-term use of metoprolol. Beta blockers which can be associated with the SEP are propanolol, timolol, metoprolol, and atenolol. The mechanism by which beta blockers causes SEP includes enhanced collagen production or an allergic reaction to the drug.[8]\n\nCirrhosis results in portal hypertension which leads to the development of collaterals around the liver. In cocoon abdomen, these small collaterals infiltrate the fibrotic tissue which can result in massive blood loss during the surgery. Therefore, probably our patient bled massively despite normal thromboelastography. Preoperative diagnosis and appropriate preparation for cocoon abdomen can help improve the postoperative morbidity and mortality in such patients.\n\nCocoon abdomen should be suspected in a patient with chronic liver disease with previous history of tuberculosis of any part of the body. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly showed that such types of patients can be taken up for live donor liver transplantation surgery with a precaution to start donor hepatectomy only after the surgeon has assessed the difficulty status of recipient hepatectomy.\n\nInformed consent\nWritten informed consent was obtained from the patient.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Rastogi R Abdominal cocoon secondary to tuberculosis Saudi JGastroenterol 2008 14 139 41 19568523 \n2 Wei B Wei HB Guo WP Zheng ZH Huang Y Hu BG Diagnosis andtreatmentofabdominal cocoon: A report of 24 cases Am J Surg 2009 198 348 53 19217609 \n3 Singh B Gupta S Abdominal cocoon: A case series Int J Surg 2013 11 325 8 23459185 \n4 Debi U Ravisankar V Prasad KK Abdominal tuberculosis of the gastrointestinal tract: Revisited World J Gastroenterol 2014 20 14831 40 25356043 \n5 Lin CH Yu JC Chen TW Chan DC Chen CJ Hsieh CB Sclerosing encapsulatingperitonitis in a liver transplant patient: A case report World J Gastroenterol 2005 11 5412 3 16149160 \n6 Zaslavsky J Mulugeta-Gordon L Vasko I Presenza T Scattergood E Meislich D Tuberculous peritonitis in children: Two case reports highlighting the important role of imaging Radiol Case Rep 2018 13 862 6 30174770 \n7 Da Rocha EL Pedrassa BC Bormann RL Abdominal tuberculosis: A radiological review with emphasis on computed tomography and magnetic resonance imaging findings Radiol Bras 2015 48 181 91 26185345 \n8 Noh SH Ye BD So H Kim YS Suh DJ Yoon SN Sclerosing encapsulating peritonitis in a long-term propranolol user Intest Res 2016 14 375 8 27799890\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": null, "issue": "13(1)", "journal": "Saudi journal of anaesthesia", "keywords": "Cocoon abdomen; liver transplantation; living donor", "medline_ta": "Saudi J Anaesth", "mesh_terms": null, "nlm_unique_id": "101500601", "other_id": null, "pages": "75-77", "pmc": null, "pmid": "30692895", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": 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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS. 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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. 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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. 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"MAINTENANCE OF ANAESTHESIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "76", "reaction": [ { "reactionmeddrapt": "Encapsulating peritoneal sclerosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Collateral circulation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GARG N, SINDWANI G, ARORA MK, PAMECHA V. LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. SAUDI-J-ANAESTH 2019?13(1):75-77.", "literaturereference_normalized": "living donor liver transplantation in a patient with cocoon abdomen anesthesia concerns", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190205", "receivedate": "20190205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15918343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" } ]
{ "abstract": "BACKGROUND\nACTH-independent Cushing's Syndrome (AICS) accounts for 15-20% of cases of Cushing's syndrome, with <1% due to abnormal receptors. Our aim is to study the presence of abnormal receptors in subjects diagnosed with AICS with nodular adrenal hyperplasia in a 14-year period (2002-2016), as well as its clinical-biological and evolutive characteristics.\n\n\nMETHODS\nA multicentre descriptive study of a 15-case series of AICS with nodular adrenal hyperplasia (study period: 2002-2016). In these cases, abnormal receptor screening was performed by means of stimulation tests, with a plasma cortisol increase of ≥ 25% from baseline being considered pathologic.\n\n\nRESULTS\nOf the 15 cases, 13 were female, with a mean age at diagnosis of 56.8 years. In 12 of the 15 cases studied, positivity was detected with stimulation tests, and, of them, 25% were positive for the meal test, 58.3% for posture walking test, 33.3% for desmopressin; 25% for terlipressin; 33.3% for GnRH; 25% for LH and 50% for metoclopramide. Regarding treatment, bilateral adrenalectomy was performed in 16.7% and unilateral adrenalectomy in 41.7%. The rest continue under observation with periodic follow-up (41.7%).\n\n\nCONCLUSIONS\nIn most of the cases studied with AICS and nodular adrenal hyperplasia (80%), an abnormal cortisol response is detected due to the presence of abnormal receptors. The test with the highest percentage of positivity was the postural walking test (58.3%).", "affiliations": "Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Endocrinología y Nutrición, Hospital Marina Baixa, Villajoyosa (Alicante), España.;Endocrinología y Nutrición, Hospital de Gandía, Gandía (Valencia), España.;Endocrinología y Nutrición, Hospital de Dénia, Dénia (Alicante).;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España; Departamento de Medicina, Universidad de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). Electronic address: sergio.martinez@uv.es.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España; Departamento de Medicina, Universidad de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM).", "authors": "Ferri\|Jordi\|J\|;Perelló\|Eva\|E\|;Lorente\|Rosario I\|RI\|;Argente\|Carlos\|C\|;Rossetti\|Paolo\|P\|;Pedro\|Teresa\|T\|;Martinez-Hervas\|Sergio\|S\|;Real\|José T\|JT\|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.1016/j.endinu.2019.07.005", "fulltext": null, "fulltext_license": null, "issn_linking": "2530-0180", "issue": "67(4)", "journal": "Endocrinologia, diabetes y nutricion", "keywords": "Abnormal receptors; Cushing's syndrome; Hiperplasia suprarrenal nodular; Nodular adrenal hyperplasia; Receptor anómalo; Síndrome de Cushing", "medline_ta": "Endocrinol Diabetes Nutr (Engl Ed)", "mesh_terms": "D000311:Adrenal Glands; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "101717565", "other_id": null, "pages": "245-252", "pmc": null, "pmid": "31672533", "pubdate": "2020-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Study of abnormal adrenal receptors in subjects with ACTH-independent Cushing's syndrome and nodular adrenal hyperplasia.", "title_normalized": "study of abnormal adrenal receptors in subjects with acth independent cushing s syndrome and nodular adrenal hyperplasia" }	[ { "companynumb": "ES-TOLMAR, INC.-19ES001143", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUBCUTANEOUS INJECTION", "drugdosagetext": "3.75 MG Q 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELIGARD" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic product effect incomplete", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERRI J , PERELL? E, LORENTE RI, ARGENTE C, ROSSETTI P, PEDRO T, ET AL. STUDY OF ABNORMAL ADRENAL RECEPTORS IN SUBJECTS WITH ACTH-INDEPENDENT CUSHING^S SYNDROME AND NODULAR ADRENAL HYPERPLASIA. 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STUDY OF ABNORMAL ADRENAL RECEPTORS IN SUBJECTS WITH ACTH-INDEPENDENT CUSHING^S SYNDROME AND NODULAR ADRENAL HYPERPLASIA. ENDOCRINOLOGIA, DIABETES Y NUTRICION. 2019?.", "literaturereference_normalized": "study of abnormal adrenal receptors in subjects with acth independent cushing s syndrome and nodular adrenal hyperplasia", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "ES", "receiptdate": "20191217", "receivedate": "20191212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17146216, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in rapidly proliferating hematological malignancies and solid tumors prior to initiating cytotoxic therapy. We encountered a patient who originally presented with diffuse lymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities suggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed blastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney injury (AKI) and uric acid had improved with intravenous fluids and the initiation of allopurinol. However, after beginning chemotherapy, the patient developed a second AKI concerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not require renal replacement therapy. With the exception of case reports, there is limited evidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based guidelines are available to guide use of rasburicase, an uricase enzyme, before initiation of chemotherapy for certain malignancies when risk for TLS is considered high. Despite these guidelines, the role of rasburicase in preventing AKI remains controversial after inconclusive results in a meta-analysis. The causative relationship between uric acid and AKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by which uric acid may cause AKI without tubular obstruction related to acute hyperuricemic nephropathy. Further characterization of the role of uric acid in causing AKI in patients without tubular obstruction may identify new mechanisms of injury and offer insight into new treatment strategies.", "affiliations": "University of Florida, Gainesville, FL, USA.;University of Florida, Gainesville, FL, USA.", "authors": "Patel\|Vishal\|V\|0000-0003-3759-9523;Case\|Robert\|R\|", "chemical_list": "C469709:rasburicase; D014527:Uric Acid; D014503:Urate Oxidase", "country": "United States", "delete": false, "doi": "10.1177/2324709620944709", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620944709\n10.1177_2324709620944709\nCase Report\nSpontaneous Tumor Lysis Syndrome in Blastoid-Variant Mantle Cell Lymphoma:\nConsiderations for the General Internist\nhttps://orcid.org/0000-0003-3759-9523Patel Vishal MD1 Case Robert MD1 1 University of Florida, Gainesville, FL,\nUSA\nRobert Case, MD, Department of Internal Medicine,\nUniversity of Florida, 1600 SW Archer Road, Rm 4101, PO Box 100277, Gainesville, FL 32610,\nUSA. Email: Robert.Case@medicine.ufl.edu\n28 7 2020 \nJan-Dec 2020 \n8 232470962094470912 5 2020 15 6 2020 21 6 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in\nrapidly proliferating hematological malignancies and solid tumors prior to initiating\ncytotoxic therapy. We encountered a patient who originally presented with diffuse\nlymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities\nsuggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed\nblastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney\ninjury (AKI) and uric acid had improved with intravenous fluids and the initiation of\nallopurinol. However, after beginning chemotherapy, the patient developed a second AKI\nconcerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not\nrequire renal replacement therapy. With the exception of case reports, there is limited\nevidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based\nguidelines are available to guide use of rasburicase, an uricase enzyme, before initiation\nof chemotherapy for certain malignancies when risk for TLS is considered high. Despite\nthese guidelines, the role of rasburicase in preventing AKI remains controversial after\ninconclusive results in a meta-analysis. The causative relationship between uric acid and\nAKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by\nwhich uric acid may cause AKI without tubular obstruction related to acute hyperuricemic\nnephropathy. Further characterization of the role of uric acid in causing AKI in patients\nwithout tubular obstruction may identify new mechanisms of injury and offer insight into\nnew treatment strategies.\n\ntumor lysis syndromeuric acid nephropathyrasburicasecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nTumor lysis syndrome (TLS) is an oncologic emergency that often develops after initiating\nchemotherapy for hematologic malignancies and lymphomas with a high proliferation rate and\nsensitivity to chemotherapy.1,2 The elevated\nlevels of uric acid may lead to acute renal failure through multiple mechanisms including\nobstruction by precipitated uric acid crystals, cytokine release syndrome, and a decreased\nglomerular filtration rate.3-5 The Cairo-Bishop definition of TLS, which\ndescribes both laboratory and clinical TLS, was developed in 2004 to help clinicians\nidentify the diagnosis and grade its severity.6 Laboratory TLS is defined by multiple electrolyte abnormalities including\nhyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.7 Clinical TLS is determined by electrolyte changes plus a medical complication such as\nrenal failure, seizure, or cardiac arrhythmia.\n\nSpontaneous TLS (SPTLS) is a rare phenomenon that can develop in high-grade non-Hodgkin\nlymphomas and hematological malignancy due to rapid proliferation of malignant cells and auto-lysis.1 In this article, we describe a case that resulted in a diagnosis of blastoid-variant\nmantle cell lymphoma (MCL), with acute kidney injury (AKI) and a uric acid level of more\nthan 20 mg/dL at the time of presentation.\n\nCase Presentation\nA 62-year-old male presented to the emergency department with a 2-week history of\nprogressive shortness of breath with exertion. His medical history was relevant for\nβ-thalassemia minor, hypertension, and a 40-year pack history of tobacco use. He initially\nhad shortness of breath with a productive cough and was provided with a brief course of\nazithromycin by an outpatient physician. While he experienced relief from the cough, his\nexertional dyspnea continued to worsen, and he developed profound fatigue and night sweats.\nIn the days preceding hospital admission, he reported a noticeable reduction in his urine\noutput, which was associated with painless abdominal distention.\n\nHis initial blood counts showed leukocytosis to 21 000/mm3 with 10% lymphocytes\nand many atypical lymphocytes. He was also found to be thrombocytopenic to 42\n000/mm3. His initial creatinine was 3.37 mg/dL with blood urea nitrogen (BUN)\nof 44 mg/dL and initial potassium level of 5.8 mEq/L and phosphorus of 6.4 mg/dL. The\nurinalysis was largely normal with a pH of 5.0, specific gravity of 1.015, and no protein or\nreported crystals. Computed tomography scans of the chest, abdomen, and pelvis were obtained\nand revealed extensive lymphadenopathy both above and below the diaphragm. There was no\nevidence of ureteral obstruction on imaging. The largest lymph node was 1.9 cm in diameter,\nand the spleen was enlarged to 23 cm. Uric acid and lactate dehydrogenase (LDH) levels were\nthen obtained and revealed a uric acid level of 20 mg/dL and LDH of more than 1600 IU/L.\n\nThe AKI and acute presentation of dyspnea led to concern for sepsis at presentation. Broad\nspectrum antibiotics were started, but then discontinued when imaging ruled out\nconsolidations and when there were no infection found in the urinary tract. The patient\ndenied use of nonsteroidal anti-inflammatory drugs and was not exposed to contrast or other\nnephrotoxins prior to admission. The patient did report oliguria prior to admission and\nafter fluid resuscitation, his renal function gradually improved to 1.2 mg/dL from 3.37mg/dL\nin 8 days (Figure 1a). During this\nperiod of time, his uric acid decreased to 3.0 mg/dL from 21.7 mg/dL (Figure 1b). He was then transferred to the inpatient\noncology team while histology results from an axillary lymph node biopsy were pending.\n\nFigure 1. (a) Trend of creatinine during first 8 days of admission. (b) Trend in uric acid during\nfirst 8 days of admission.\n\nBoth the lymph node biopsy and peripheral flow cytometry revealed findings consistent with\nblastoid-variant MCL. The Ki67 of the specimen was greater than 90%. With concern that he\nwould develop an AKI on initiation of chemotherapy, he was preemptively started on\ncontinuous normal saline 200 mL/h and allopurinol at a dose of 300 mg 3 times daily. Due to\nthe improvement of his uric acid at the time, he did meet our hospital criteria to receive\nrasburicase prior to the initiation of chemotherapy. Chemotherapy with rituxumab and\nhyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone) was initiated. The\npatient remained on allopurinol while receiving chemotherapy.\n\nWithin 24 hours of beginning chemotherapy, the potassium, phosphate, and BUN levels rose\nsignificantly. The creatinine then began to increase with a peak of 2.69 mg/dL and a BUN of\n105 mg/dL. During the 48 hours immediately after starting chemotherapy, the potassium level\nincreased to more than 6.2 mEq/L and the phosphorus level to 12 mg/dL. The uric acid\nincreased minimally from 3 to 4 mg/dL. The patient continued to produce urine and responded\nto medical therapy primarily targeting hyperkalemia. Dialysis was not required, and as the\nchemotherapy cycle concluded, renal function started to improve after 3 days and creatinine\ntrended to a new baseline of 0.7 mg/dL.\n\nDiscussion\nFor patients with newly diagnosed lymphoma, risk for development of TLS is stratified from\nlow to high based on the anticipated aggressiveness of the malignancy and its anticipated\nsensitivity to chemotherapy.1,8 As it\npertains to the patient we have described, MCL of the blastoid variant subtype is considered\nhigh risk for TLS in cases where the LDH level is more than twice the upper limit of normal.9 On review, the presenting renal dysfunction, uric acid level of more than 20 mg/dL\nand hyperkalemia, with an ultimate diagnosis of an aggressive non-Hodgkin’s lymphoma, is\nclinically consistent with a diagnosis of spontaneous TLS. In our review of the literature,\nwe did not identify other examples of SPTLS with blastoid-variant lymphoma. SPTLS is a rare,\nbut accepted phenomenon that is thought to occur only in rapidly proliferating non-Hodgkin’s\nlymphomas and hematological malignancies.1 Since many cases of SPTLS can mimic other acute non-neoplastic diseases processes,\nthe diagnosis is challenging to confirm without malignant pathology. Additionally, consensus\nguidelines are not available to guide the general medicine clinician on how to specifically\nmanage the renal dysfunction associated with this condition.\n\nFor patients with SPTLS or standard TLS, uric acid elevation is thought to be the cause of\nAKI with most cases involving deposition of uric acid crystals in the nephron resulting in\nobstruction and increased tubular pressure.10,11 Increased tubular pressure directly\ndecreases filtration at the glomerulus. Ultimately, the inability to excrete water and\nelectrolytes may lead to uncontrollable electrolyte abnormalities and fluid overload, which\ncan subsequently result in an urgent requirement for dialysis. In our case, we initially\nassumed uric acid had caused the patient’s AKI by the mechanism described above; however,\nboth ultrasound and computed tomography imaging did not demonstrate evidence of\nnephrolithiasis. Furthermore, the gradual improvement of renal function and continued urine\noutput also left us questioning this classical mechanism of kidney injury. This led to our\nreview of alternative causes of AKI related to hyperuricemia.\n\nDuring the workup of our patient, urine eosinophils were absent, and urine microscopic\nanalysis did not reveal pathologic casts. Additionally, the patient had oliguria rather than\nanuria and did not require dialysis. For these reasons, the patient’s acute uric acid\nnephropathy and AKI were the result of elevated uric acid levels, but more likely due to\ncrystal independent mechanisms.4,10,12 Using animal models, uric\nacid has been shown to contribute to AKI by impairing renal autoregulation, the\nbioavailability of nitric oxide, and proximal tubular proliferation.4,13,14 Hahn et al10 reviewed this topic and described how elevated uric acid levels are associated with\nelevated levels of inflammatory mediators systemically and in the nephron. The release of\ncytokines including monocyte chemoattractant protein-1, tumor necrosis factor-α, and\nintercellular adhesion molecule 1 have been implicated in the nephrotoxicity that uric acid\npotentiates. In a rat model, mild hyperuricemia has also been described as causing a 50%\nreduction in glomerular filtration rate and renal blood flow.10,13 Uric acid impairs the bioavailability of\nnitric oxide, which results in further renal tissue ischemia through vasoconstriction.14 Considering these models for renal injury, future therapies may be developed to treat\ncrystal-independent renal dysfunction related to hyperuricemia.\n\nThe current standard for management of renal failure in TLS is based on minimizing tubular\nobstruction, diluting crystals, and preventing uric acid crystal formation by providing\nintravenous fluid and uric acid lowering therapy in the form of allopurinol or rasburicase.\nUse of allopurinol, as in our case, is beneficial in preventing uric acid production but\ndoes not reduce the level of uric acid if already elevated.15 Expert guidelines recommend use of rasburicase, a urate oxidase enzyme, for high-risk\npatients before initiating chemotherapy.11,16 For patients with spontaneous TLS, we did\nnot identify any clear expert-based guidelines for clinicians. This may be due to the rarity\nof the condition or the possibility of confounding causes of AKI unrelated to uric acid\nelevation. Use of rasburicase to prevent AKI seems physiologically intuitive, but high-level\nclinical evidence to support this effect is not present to date. In a nonrandomized study of\npediatric patients at high risk for developing TLS, one group trended changes in uric acid\nand creatinine while receiving either rasburicase or allopurinol, and the results favored\nimproved renal outcomes with the use of rasburicase.17 There has been one clinical trial evaluating the use of rasburicase in adult patients\nat risk for TLS, and the results did not show a reduced risk of developing an AKI. The study\ndid, however, show that rasburicase correlated with reduced laboratory TLS.18 There has been one meta-analysis performed in review of rasburicase based mostly on\ntrials in pediatric patients. Despite 5 pediatric trials showing a benefit in favor of\nrasburicase, it was determined that evidence was insufficient to promote the use of\nrasburicase to prevent TLS or AKI due to the inconclusive findings in a single randomized\nclinical trial.19 For our case, there is no evidence to guide a decision on whether or not to use\nrasburicase. Our case adds to a growing need to conduct randomized trials evaluating the use\nof rasburicase in both SPTLS and TLS.\n\nSummary\nIn summary, we have reported the first case of SPTLS in a patient with blastoid-variant\nMCL. We have reviewed the limitations, which many non-oncologist providers may encounter on\nrealization of this condition. Development of consensus diagnostic criteria and management\nguidelines for spontaneous TLS would be of benefit for non-oncology, general medicine\nproviders. More robust evidence is needed to clarify the role of rasburicase in patients at\nrisk for TLS and in theory, for those with SPTLS.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: At the University of Florida, institutional review board or ethic board approval is not\nrequired for publication of case reports that do not disclose identifiable patient\ninformation.\n\nInformed Consent: Written informed consent and verbal consent was obtained from the patient for their\nanonymized information to be published in this article.\n\nORCID iD: Vishal Patel \nhttps://orcid.org/0000-0003-3759-9523\n==== Refs\nReferences\n1 \nHande KR Garrow GC. \nAcute tumor lysis syndrome in patients with high-grade non-Hodgkin’s\nlymphoma\n. Am J Med .\n1993 ;94 :133 -139\n.8430709 \n2 \nMontesinos P Lorenzo I Martín G , et al\nTumor lysis syndrome in patients with\nacute myeloid leukemia: identification of risk factors and development of a predictive\nmodel\n. Haematologica .\n2008 ;93 :67 -74\n.18166787 \n3 \nKjellstrand CM Cambell DC von Hartitzsch B Buselmeier TJ. \nHyperuricemic acute renal failure\n. Arch Intern\nMed \n1974 ;\n133 :349 -359\n.4283735 \n4 \nShimada M Dass B Ejaz AA. \nParadigm shift in the role of uric acid in acute kidney\ninjury\n. Semin Nephrol .\n2011 ;31 :453 -458\n.22000653 \n5 \nShimabukuro-Vornhagen A Gödel P Subklewe M , et al\nCytokine release\nsyndrome\n. J Immunother Cancer .\n2018 ;6 :56 .29907163 \n6 \nCairo MS Bishop M. \nTumour lysis syndrome: new therapeutic strategies and\nclassification\n. Br J Haematol .\n2004 ;127 :3 -11\n.15384972 \n7 \nHoward SC Jones DP Pui CH. \nThe tumor lysis syndrome\n. N Engl J Med .\n2011 ;364 :1844 -1854\n.21561350 \n8 \nMato AR Riccio BE Qin L , et al\nA predictive model for the detection\nof tumor lysis syndrome during AML induction therapy\n. Leuk\nLymphoma .\n2006 ;47 :877 -883\n.16753873 \n9 \nCairo MS Coiffier B Reiter A Younes A ; TLS Expert Panel . Recommendations for the\nevaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children\nwith malignant diseases: an expert TLS panel consensus\n. Br J\nHaematol .\n2010 ;149 :578 -586\n.20331465 \n10 \nHahn K Kanbay M Lanaspa MA Johnson RJ Ejaz AA. \nSerum uric acid and acute kidney injury: a mini review\n.\nJ Adv Res .\n2017 ;8 :529 -536\n.28748118 \n11 \nDarmon M Vincent F Camous L , et al; Groupe de Recherche en Réanimation\nRespiratoire et Onco-Hématologique (GRRR-OH) . Tumour lysis\nsyndrome and acute kidney injury in high-risk haematology patients in the rasburicase\nera. A prospective multicentre study from the Groupe de Recherche en Réanimation\nRespiratoire et Onco-Hématologique\n. Br J Haematol .\n2013 ;162 :489 -497\n.23772757 \n12 \nShimada M Johnson RJ May WS Jr , et al\nA novel role for uric acid in acute\nkidney injury associated with tumour lysis syndrome\n. Nephrol\nDial Transplant .\n2009 ;24 :2960 -2964\n.19581334 \n13 \nSánchez-Lozada LG Tapia E Santamaría J , et al\nMild hyperuricemia induces\nvasoconstriction and maintains glomerular hypertension in normal and remnant kidney\nrats\n. Kidney Int .\n2005 ;67 :237 -247\n.15610247 \n14 \nKang DH Park SK Lee IK Johnson RJ. \nUric acid-induced C-reactive protein expression: implication on cell\nproliferation and nitric oxide production of human vascular cells\n.\nJ Am Soc Nephrol .\n2005 ;16 :3553 -3562\n.16251237 \n15 \nPacher P Nivorozhkin A Szabó C. \nTherapeutic effects of xanthine oxidase inhibitors: renaissance half a\ncentury after the discovery of allopurinol\n. Pharmacol\nRev .\n2006 ;58 :87 -114\n.16507884 \n16 \nCoiffier B Altman A Pui CH Younes A Cairo MS. \nGuidelines for the management of pediatric and adult tumor lysis syndrome:\nan evidence-based review\n. J Clin Oncol .\n2008 ;26 :2767 -2778\n.18509186 \n17 \nGoldman SC Holcenberg JS Finklestein JZ , et al\nA randomized comparison between\nrasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor\nlysis\n. Blood .\n2001 ;97 :2998 -3003\n.11342423 \n18 \nCortes J Moore JO Maziarz RT , et al\nControl of plasma uric acid in adults\nat risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and\nrasburicase followed by allopurinol compared with allopurinol alone—results of a\nmulticenter phase III study\n. J Clin Oncol .\n2010 ;28 :4207 -4213\n.20713865 \n19 \nCheuk DK Chiang AK Chan GC Hay SY. \nUrate oxidase for the prevention and treatment of tumour lysis syndrome in\nchildren with cancer\n. Cochrane Database Syst Rev .\n2017 ;(3 ): CD006945 .28272834\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "rasburicase; tumor lysis syndrome; uric acid nephropathy", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D058186:Acute Kidney Injury; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome; D014503:Urate Oxidase; D014527:Uric Acid", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620944709", "pmc": null, "pmid": "32720820", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28272834;16251237;29907163;19581334;20331465;15384972;4283735;18166787;28748118;20713865;18509186;23772757;15610247;22000653;16507884;21561350;8430709;16753873;11342423", "title": "Spontaneous Tumor Lysis Syndrome in 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SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID?VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RASBURICASE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40069", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HYPER-CVAD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCTIVE COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSPNOEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "PATEL V, CASE R. SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID-VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020?8:1-5. DOI:10.1177/2324709620944709", "literaturereference_normalized": "spontaneous tumor lysis syndrome in blastoid variant mantle cell lymphoma considerations for the general internist", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201119", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18178693, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]
{ "abstract": "In cases of severe acetaminophen-induced acute liver failure and hepatic encephalopathy, liver transplant can be the only real hope for neurologic recovery and indeed survival. In such cases, the bioethical principles of beneficence and justice often come into conflict. This article examines a case in which a neurologist managing an acetaminophen-overdose patient in the neurologic intensive care unit is faced with a conflict between her patient's need for a liver transplant and the needs of other patients on the transplant list.", "affiliations": null, "authors": "Willey\|Joshua Z\|JZ\|;Tolchin\|Benjamin David\|BD\|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1212/01.CON.0000450974.91699.b8", "fulltext": null, "fulltext_license": null, "issn_linking": "1080-2371", "issue": "20(3 Neurology of Systemic Disease)", "journal": "Continuum (Minneapolis, Minn.)", "keywords": null, "medline_ta": "Continuum (Minneap Minn)", "mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D026686:Beneficence; D062787:Drug Overdose; D006501:Hepatic Encephalopathy; D006801:Humans; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012935:Social Justice", "nlm_unique_id": "9509333", "other_id": null, "pages": "681-5", "pmc": null, "pmid": "24893242", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Liver transplant for intentional acetaminophen overdose and hepatic encephalopathy: a conflict between beneficence and justice.", "title_normalized": "liver transplant for intentional acetaminophen overdose and hepatic encephalopathy a conflict between beneficence and justice" }	[ { "companynumb": "PHHY2015US036277", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETYLCYSTEINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLCYSTEINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MANNITOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MANNITOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAXIMIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAXIMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LACTULOSE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACTULOSE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WILLEY JZ, TOLCHIN BD.. LIVER TRANSPLANT FOR INTENTIONAL ACETAMINOPHEN OVERDOSE AND HEPATIC ENCEPHALOPATHY: A CONFLICT BETWEEN BENEFICENCE AND JUSTICE.. CONTINUUM LIFELONG LEARNING IN NEUROLOGY. 2014;20(3):681-685", "literaturereference_normalized": "liver transplant for intentional acetaminophen overdose and hepatic encephalopathy a conflict between beneficence and justice", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150326", "receivedate": "20150326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10958193, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]
{ "abstract": "Eosinophilic dermatosis of hematological malignancy is a paraneoplastic skin eruption associated with chronic lymphocytic leukemia and other B-cell malignancies. It clinically resembles an insect bite reaction and it can precede the symptoms of the hematological malignancy or be related to a more aggressive course. Different treatments have been proposed, but partial response and recurrence are frequent. Herein, we describe a case of eosinophilic dermatosis associated with mantle cell lymphoma with remission after lenalidomide therapy.", "affiliations": "Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Oncology Center, Portuguese Beneficence of São Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.", "authors": "Sato-Sano\|Marcelo\|M\|https://orcid.org/0000-0003-2934-6729;Teixeira\|Solange Pistori\|SP\|;Vargas\|Juliano Cordova\|JC\|;Baiocchi\|Otávio Cesar Carvalho Guimarães\|OCCG\|;Enokihara\|Milvia Maria Simões E Silva\|MMSES\|;Gomes\|Elimar Elias\|EE\|;Batista\|Mariana Dias\|MD\|", "chemical_list": "D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1111/1346-8138.14916", "fulltext": null, "fulltext_license": null, "issn_linking": "0385-2407", "issue": "46(7)", "journal": "The Journal of dermatology", "keywords": "eosinophilic dermatosis of hematological malignancy; eosinophilic reactive dermatoses; hematological malignancies; lenalidomide; paraneoplastic disorders", "medline_ta": "J Dermatol", "mesh_terms": "D004802:Eosinophilia; D005076:Exanthema; D006801:Humans; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D011537:Pruritus; D012867:Skin; D016896:Treatment Outcome", "nlm_unique_id": "7600545", "other_id": null, "pages": "618-621", "pmc": null, "pmid": "31144726", "pubdate": "2019-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lenalidomide in the management of eosinophilic dermatosis of hematological malignancy.", "title_normalized": "lenalidomide in the management of eosinophilic dermatosis of hematological malignancy" }	[ { "companynumb": "PHHY2019BR126884", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "EOSINOPHILIC CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EOSINOPHILIC CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYDAUNORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, 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{ "abstract": "This case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis.", "affiliations": "Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of General Internal Medicine, Department of Medicine, Medstar Georgetown University Hospital, Washington DC, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.", "authors": "Genovese\|Leonard\|L\|https://orcid.org/0000-0002-0950-9861;Dey\|Amit K\|AK\|;Cole\|Robert T\|RT\|;Cooper\|Lauren B\|LB\|;Desai\|Shashank\|S\|;May\|Christopher W\|CW\|;Sarin\|Eric\|E\|;Shah\|Palak\|P\|;Sinha\|Shashank S\|SS\|;Psotka\|Mitchell A\|MA\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/20009666.2021.1948668", "fulltext": "\n==== Front\nJ Community Hosp Intern Med Perspect\nJ Community Hosp Intern Med Perspect\nJournal of Community Hospital Internal Medicine Perspectives\n2000-9666\nTaylor & Francis\n\n10.1080/20009666.2021.1948668\n1948668\nVersion of Record\nCase Report\nCase Report\nFulminant cardiogenic shock due to cardiac sarcoidosis\nL. GENOVESE ET AL.\nJOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES\nhttps://orcid.org/0000-0002-0950-9861\nGenovese Leonard a\nDey Amit K. b\nCole Robert T. a\nCooper Lauren B. a\nDesai Shashank a\nMay Christopher W. a\nSarin Eric a\nShah Palak a\nSinha Shashank S. a\nPsotka Mitchell A. a\na Division of Cardiology, Inova Heart and Vascular Institute , Falls Church, VA, USA\nb Division of General Internal Medicine, Department of Medicine, Medstar Georgetown University Hospital , Washington DC, USA\nCONTACT Leonard Genovese leonard.genovese@inova.org Inova Heart and Vascular Institute , 3300 Gallows Road, Falls Church, VA 22042\nTwitter: @lenny_genovese\n\nTweet: A Case of Rapidly Progressive Cardiogenic #Shock Due to Cardiac #Sarcoidosis @lenny_genovese @mpsotka @shashanksinhamd @doctorrtc @lbcooper @ihvinews\n\nABBREVIATIONS\n\nECMO: extracorporeal membrane oxygenation; LVEF: left ventricular ejection fraction; cMRI: cardiac magnetic resonance imaging\n\n20 9 2021\n2021\n20 9 2021\n11 5 673677\nIntegra13 9 2021\nIntegra13 9 2021\n26 3 2021\n23 6 2021\n© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nThis case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis.\n\nKEYWORDS\n\nCardiac sarcoidosis\nheart failure\ncardiogenic shock\nheart transplantation\n==== Body\npmc1. Case presentation\n\nA 57-year-old man with a medical history significant only for hypercholesterolemia presented to a cardiology clinic with 6 months of progressive exercise intolerance manifest as a gradual increase in his 1-mile running time and a decline from running 30 miles to less than 3 miles each week. Days later, outpatient coronary angiography showed non-obstructive coronary atherosclerosis and ventriculogram left ventricular ejection fraction (LVEF) was 45%. The patient was started on carvedilol and aspirin.\n\nOne week later, he awoke with acute left-sided chest pain. Emergent electrocardiography demonstrated sinus tachycardia and ST-segment elevations and repolarization abnormalities (Figure 1). Repeat coronary angiography revealed no change, but LVEF by ventriculography had declined to 20%. Post-procedurally, he developed hypotension requiring initiation of vasopressors and hemodynamically unstable wide-complex tachycardia requiring defibrillation. He was transferred to our hospital for further management.Figure 1. Electrocardiograms\n\nLegend: Figure A shows baseline electrocardiogram from outpatient clinic. Figure B is the electrocardiogram at presentation to hospital demonstrating ST segment elevations in the anterior precordial leads with ST segment depressions in the lateral leads.\n\nOn arrival, the patient was comfortable but mean arterial pressure was 55 mmHg off vasopressors. Jugular venous pressure was elevated, breath sounds were decreased in the bilateral lung bases, and heart sounds were distant without evidence of a murmur or gallop. His extremities were cool. Arterial blood gas showed a pH of 7.4, PaCO2 of 29 mmHg, PaO2 of 63 mmHg on ambient air, bicarbonate of 20 mEq/L, lactate of 4.0 mmol/L, troponin I of 2.0 ng/mL, B-type natriuretic peptide of 2600 pg/mL, and a creatinine of 1.4 mg/dL increased from a baseline of 1.0 mg/dL. A Swan-Ganz catheter was placed revealing a right atrial pressure of 20 mmHg and pulmonary capillary wedge pressure of 22 mmHg. Pulmonary artery oxygen saturation was 40% and calculated cardiac output using the estimated Fick formula was 2.4 L/min, with cardiac index of 1.1 L/min/m2. Given the acuity of presentation and the rapidity of clinical decline, urgent laboratory testing and imaging studies were performed.\n\nTransthoracic echocardiography showed biventricular dysfunction and dilation with global hypokinesis, without asymmetric myocardial thickening or structural valvular disease. There was biatrial dilation. Thyroid panel, cortisol, hemoglobin A1c, iron studies including ferritin, and autoimmune antibody levels were normal, while human immunodeficiency virus, Borrelia burgdorferi, respiratory viral panel, and blood culture testing were negative. Urinary toxicology was negative. C-reactive protein was elevated at 13.9 mg/dL. Cardiac myocardial resonance imaging (cMRI) demonstrated patchy gadolinium delayed enhancement within the right and left ventricular myocardia and pericardial thickening with enhancement, consistent with myocarditis or infiltrative disease though without T2-weighted evidence of edema (Figure 2). Endomyocardial biopsy was not pursued due to the patient’s hemodynamic and electrical instability.Figure 2. Cardiac magnetic resonance imaging\n\nLegend: Cardiac magnetic resonance imaging with myocardial delayed gadolinium enhancement in T1 weighted imaging: Figure A, anterior right ventricular enhancement (red arrow). Figure B, pericardial thickening with pericardial enhancement (blue arrows).\n\nFigure 3. Photomicrographs of explanted cardiac myocardium\n\nLegend: Figure A: Right ventricular myocardium with large areas of hypercellularity and extensive fibrosis (red arrows) with granuloma formation (blue arrows). Figure B: Left ventricular granulomas (blue arrows) with surrounding fibrosis and hypercellularity.\n\nMilrinone and furosemide infusions were initiated, nitroprusside was added, and an intra-aortic balloon pump was eventually implanted for persistent cardiogenic shock (Table 1). He remained oliguric, and continued to have atrial and ventricular arrhythmias requiring defibrillation despite amiodarone infusion. Though the differential diagnoses of sarcoidosis and giant cell myocarditis were discussed, the patient was not initiated on corticosteroids. Due to continued hemodynamic and electrical instability he was femorally cannulated for veno-arterial extracorporeal membrane oxygenation (ECMO). Upon transplantation, pathological examination of the explanted heart revealed diffuse biventricular fibrosis, non-caseating granulomas, and multi-nucleated giant cells consistent with severe cardiac sarcoidosis (Figure 3).Table 1. Invasive hemodynamics\n\nIntervention\tLactate (mmol/L)\tMAP\n(mmHg)\tRAP\n(mmHg)\tPAP\n(mmHg)\tPAWP\n(mmHg)\tSvO2\n(%)\tCO/CI\n(Fick)\t\nNone\t4.0\t85\t20\t30/17\n(mean 25)\t22\t40\t2.38/1.13\t\nMilrinone\n0.5 mcg/kg/min\t3.4\t80\t18\t32/22\n(mean 25)\t22\t57\t3.43/1.63\t\n+ Nitroprusside 3 mcg/kg/min\t3.7\t71\t12\t30/21\n(mean – 24)\t21\t50\t3.59/1.71\t\n+ IABP at 1:1\t5.1\t64\t13\t27/13\n(mean – 18)\t10\t37\t3.05/1.45\t\nMAP = Mean arterial pressure; SvO2 = Mixed venous oxygen saturation; CO/CI = Cardiac output/cardiac index; IABP = intra-aortic balloon pump; PAP = Pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; RAP = right atrial pressure\n\nThe patient was discharged home from the hospital two weeks after transplant and continues to do well. He has completed cardiac rehabilitation and started running again. His immunosuppression regimen consists of prednisone 5 mg daily, tacrolimus 2 mg twice daily, and mycophenolate 1000 mg twice daily. He has not had allograft rejection.\n\n2. Discussion\n\nSarcoidosis is a multisystem granulomatous disease of unknown etiology that may affect any organ system. It has an estimated prevalence of about 200,000 people in the USA [1]. Noncaseating granulomas are the pathologic hallmark of the disease, and it most commonly presents with pulmonary and lymphatic disease. Although autopsy studies have uncovered cardiac involvement in 25% of patients with sarcoidosis, the true prevalence may be underappreciated [1]. The three principal sequelae of myocardial damage due to sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure, which can be insidious or fulminant [1]. Diagnosis of CS can be challenging, as there are multiple proposed clinical criteria without a gold standard [1]. Nevertheless, the mainstays of diagnosis include cardiac MRI with gadolinium for myocardial fibrosis and edema, and fluorodeoxyglucose positron emission tomography for myocardial inflammation. Endomyocardial biopsy has excellent specificity but an estimated sensitivity of less than 30%, and some severe cases are only diagnosed post-mortem.\n\nPatients with CS generally have a poorer prognosis than patients with sarcoidosis but without cardiac involvement, and left ventricular function appears to predict survival. Of patients with CS and normal ventricular function 89% survive to 10 years compared to 27% of patients with systolic dysfunction [1]. The diffuse myocardial fibrosis and granulomas with biventricular dilation and dysfunction in this case are consistent with longstanding unrecognized and life-threatening disease.\n\nThe mainstay of treatment for CS includes immunosuppression, typically with corticosteroids and variably with steroid-sparing agents such as methotrexate or infliximab [2]. In combination with immunosuppression, antiarrhythmic medications including amiodarone or sotalol and ablation procedures can be used for CS-associated ventricular arrhythmias. However, ventricular tachycardia ablation in CS has had varied success and frequently is associated with recurrence [3,4] because of ongoing inflammation or progressive myocardial scarring. Given the propensity for ventricular arrhythmias and risk of sudden cardiac death, implantable cardioverter-defibrillator therapy may be considered in a broad array of situations according to expert consensus recommendations [5]. Orthotopic heart transplant may be indicated in severe cases of CS unresponsive to drug and device therapy. CS recurrence after transplant is rare and may be prevented with long-term corticosteroid use. Nevertheless, patients with CS have similar rates of rejection and overall survival as patients transplanted due to other cardiomyopathies [2].\n\n3. Conclusions\n\nCardiac sarcoidosis rarely presents as refractory cardiogenic shock. This case highlights the need to include CS in the differential diagnosis of patients with cardiomyopathy, even if there is no evidence of extracardiac disease. Findings on advanced cardiac imaging can help determine the potential etiology of a non-ischemic cardiomyopathy, including sarcoidosis. Though he presented acutely, in this case CS was likely progressive over a longer period of time than his months of symptoms, and perhaps could have been treated with immunosuppression if identified earlier.\n\n4. Learning objectives\n\nCardiac sarcoidosis may be difficult to diagnose and can present as rapidly progressive heart failure with cardiogenic shock.\n\nYoung patients with an otherwise unknown etiology of cardiomyopathy would likely benefit from advanced cardiac imaging with FDG-PET or MRI, which may assist with diagnosis if a high diagnostic suspicion of cardiac sarcoidosis or other infiltrative disease is maintained.\n\nThe three most common presentations of cardiac sarcoidosis are heart failure, ventricular arrhythmias, and conduction abnormalities.\n\nThe mainstays of therapy for cardiac sarcoidosis include immunosuppression with corticosteroids and frequently steroid-sparing agents.\n\nAmiodarone and sotalol are the most common antiarrhythmics used to suppress ventricular arrhythmias; ventricular ablation has demonstrated mixed results.\n\nSevere refractory cardiac sarcoidosis may require heart transplantation though sarcoidosis can recur in the donor heart.\n\nDisclosure statement\n\nNo potential conflict of interest was reported by the author(s).\n==== Refs\nReferences\n\n[1] Ribeiro NetoML, JellisCL, JoyceE, et al. Update in cardiac sarcoidosis. Ann Am Thorac Soc. 2019 Nov;16 (11 ):1341–1350. .31322914\n[2] RosenthalDG, AndersonME, PetekBJ, et al. Invasive hemodynamics and rejection rates in patients with cardiac sarcoidosis after heart transplantation. Can J Cardiol. 2018 Aug;34 (8 ):978–982. Epub 2018 Apr 6. .30049365\n[3] JeficD, JoelB, GoodE, et al. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry. Heart Rhythm. 2009 Feb;6 (2 ):189–195. Epub 2008 Oct 30.19187909\n[4] KoplanBA, SoejimaK, BaughmanK, et al. Refractory ventricular tachycardia secondary to cardiac sarcoid: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm. 2006 Aug;3 (8 ):924–929. Epub 2006 Mar 30.16876741\n[5] BirnieDH, SauerWH, BogunF, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014 July;11 (7 ):1305–1323. Epub 2014 May 9.24819193\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2000-9666", "issue": "11(5)", "journal": "Journal of community hospital internal medicine perspectives", "keywords": "Cardiac sarcoidosis; cardiogenic shock; heart failure; heart transplantation", "medline_ta": "J Community Hosp Intern Med Perspect", "mesh_terms": null, "nlm_unique_id": "101601396", "other_id": null, "pages": "673-677", "pmc": null, "pmid": "34567462", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "19187909;16876741;30049365;24819193;31322914", "title": "Fulminant cardiogenic shock due to cardiac sarcoidosis.", "title_normalized": "fulminant cardiogenic shock due to cardiac sarcoidosis" }	[ { "companynumb": "US-DRREDDYS-USA/USA/20/0121992", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM NITROPRUSSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "210114", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIOGENIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM NITROPRUSSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MILRINONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIOGENIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MILRINONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIOGENIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GENOVESE L, DEY A, COLE R, COOPER L, DESAI S, MAY C, SARIN E, SHAH P, SINHA S, PSOTKA M. 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{ "abstract": "Mycobacterium avium-intracellulare complex (MAC) infections are well known in immunocompromised patients, notably in human immunodeficiency virus infection, but remain scarcely described in kidney transplantation. Moreover, cutaneous involvement in this infection is very unusual. We describe here a disseminated infection caused by MAC in a kidney transplant recipient revealed by cutaneous lesions. This case highlights the need for an exhaustive, iterative microbiologic workup in the context of an atypical disease presentation in a renal transplant patient, regardless of the degree of immunosuppression.", "affiliations": "Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Service d'anatomopathologie, Hôpital Cochin, Université Paris Descartes, APHP, Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Service d'hépatologie, Hôpital Cochin, Université Paris Descartes, APHP, Paris, France.;Service de dermatologie, Hôpital Cochin, Pavillon Tarnier, Université Paris Descartes, APHP, Paris, France.;Service de transplantation rénale, Hôpital Necker Enfants Malades, Université Paris Descartes, APHP, Paris, France.;Service de dermatologie, Hôpital Cochin, Pavillon Tarnier, Université Paris Descartes, APHP, Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.", "authors": "Fadlallah\|J\|J\|;Rammaert\|B\|B\|;Laurent\|S\|S\|;Lanternier\|F\|F\|;Pol\|S\|S\|;Franck\|N\|N\|;Mamzer\|M F\|MF\|;Dupin\|N\|N\|;Lortholary\|O\|O\|", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/tid.12478", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "18(1)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "Mycobacterium avium-intracellulare complex; cutaneous infection; immunodeficiency; kidney transplantation; non-tuberculous mycobacteria", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D066027:Transplant Recipients", "nlm_unique_id": "100883688", "other_id": null, "pages": "105-11", "pmc": null, "pmid": "26540585", "pubdate": "2016-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Mycobacterium avium complex disseminated infection in a kidney transplant recipient.", "title_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient" }	[ { "companynumb": "FR-TEVA-644573ISR", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, 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"RIFABUTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016; 18(1): 105-111", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160411", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12191524, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-WATSON-2016-05976", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE (UNKNOWN)" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECT DIS. 2016;18(1):105-11", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160415", "receivedate": "20160322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12200097, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-MYLANLABS-2016M1016414", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG/DAY; LAST 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG/DAY; LAST 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N, ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPL-INFECT-DIS 2016;18(1):105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160428", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12301367, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "FR-BAUSCH-BL-2016-006447", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40065", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016?18(1):105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12196970, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2016-01097", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090033", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090033", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "0202532", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GM", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078939", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LORTHOLARY O, FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, DUPIN N, FRANCK N, MAMZER M. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2015;18:105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160402", "receivedate": "20160402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12232751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-PFIZER INC-2016149359", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic cirrhosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH, J.. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016;18 (1):105-111", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161117", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12196833, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "Thrombocytosis has been feared as a source of thrombotic complications during the conduct of cardiopulmonary bypass (CPB) for patients undergoing cardiac procedures. We present a patient urgently requiring repair/replacement of three heart valves that had preexisting myelofibrosis with thrombocytosis (platelet count of 800,000 per µl) and neutrophilia (40,000 per µl). Despite achieving an activated clotting time > 500 s with heparin and antithrombin concentrate administration prior to CPB, the pump oxygenator and reservoir demonstrated significant clot just prior to restoration of the patient's circulation. The patient subsequently suffered a severe protamine reaction that was successfully managed. A review of the literature of similar patients and the relevant cellular and biochemical mechanisms in this setting are presented, with potential therapeutic approaches to prevent such complications noted.", "affiliations": "Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA. vgnielsen333@gmail.com.;Departments of Anesthesiology and Surgery, The University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA.;Perfusion Department, Banner University Medical Center Tucson, Tucson, AZ, USA.", "authors": "Nielsen\|Vance G\|VG\|http://orcid.org/0000-0002-8072-9883;Kazui\|Toshinobu\|T\|;Horn\|Evan A\|EA\|;Dotson\|Victoria E\|VE\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1007/s11239-021-02574-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0929-5305", "issue": "52(4)", "journal": "Journal of thrombosis and thrombolysis", "keywords": "Cardiopulmonary bypass; Neutrophilia; Platelet factor 4; Thrombocytosis; Thrombosis", "medline_ta": "J Thromb Thrombolysis", "mesh_terms": null, "nlm_unique_id": "9502018", "other_id": null, "pages": "1220-1226", "pmc": null, "pmid": "34581944", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": "10915475;15334759;3485946", "title": "Thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass: a case report and literature review.", "title_normalized": "thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass a case report and literature review" }	[ { "companynumb": "US-Fresenius Kabi-FK202114210", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROTAMINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089454", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Infusion", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Procoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "350", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROTAMINE SULFATE" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary hypertension", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Nielsen V, Kazui T, Horn E, Dotson V. Thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass: a case report and literature review. Journal of Thrombosis and Thrombolysis. 2021;52:1220-1226.", "literaturereference_normalized": "thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20202348, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "We report the case of a 10-year-old child treated for latent tuberculosis infection (LTBI) with pyrazinamide (PZA) and levofloxacin after contact with a smear-positive multidrug-resistant tuberculosis adult. Over the course of the treatment, the patient developed a drug-induced fulminant hepatitis attributed to the combination of PZA and levofloxacin. This case highlights the hepatotoxicity of the association of second-line anti-TB treatment in children.", "affiliations": "From the Service d'Urgences et de Réanimation Pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Service des maladies infectieuses, Hôpital de la Croix Rousse, Groupement Hospitaliser Nord, Hospices Civils de Lyon, Université Claude Bernard Lyon, Lyon, France.;Service de Pneumologie pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Bron, France.;From the Service d'Urgences et de Réanimation Pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.", "authors": "Huguet\|Annabelle\|A\|;Ader\|Florence\|F\|;Ohlmann\|Camille\|C\|;Collardeau-Frachon\|Sophie\|S\|;Gillet\|Yves\|Y\|", "chemical_list": "D000995:Antitubercular Agents; D011718:Pyrazinamide; D064704:Levofloxacin", "country": "United States", "delete": false, "doi": "10.1097/INF.0000000000002413", "fulltext": null, "fulltext_license": null, "issn_linking": "0891-3668", "issue": "38(10)", "journal": "The Pediatric infectious disease journal", "keywords": null, "medline_ta": "Pediatr Infect Dis J", "mesh_terms": "D000995:Antitubercular Agents; D002648:Child; D004359:Drug Therapy, Combination; D006801:Humans; D055985:Latent Tuberculosis; D064704:Levofloxacin; D008297:Male; D047508:Massive Hepatic Necrosis; D011718:Pyrazinamide; D018088:Tuberculosis, Multidrug-Resistant", "nlm_unique_id": "8701858", "other_id": null, "pages": "1025-1026", "pmc": null, "pmid": "31335574", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Drug-Induced Fulminant Hepatitis in a Child Treated for Latent Multidrug-Resistant Tuberculosis With Dual Therapy Combining Pyrazinamide and Levofloxacin.", "title_normalized": "drug induced fulminant hepatitis in a child treated for latent multidrug resistant tuberculosis with dual therapy combining pyrazinamide and levofloxacin" }	[ { "companynumb": "FR-TEVA-2020-FR-1213862", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076361", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "650", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076361", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LATENT TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "26", "reaction": [ { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cell death", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cholestasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HUGUET A. DRUG-INDUCED FULMINANT HEPATITIS IN A CHILD TREATED FOR LATENT MULTIDRUG-RESISTANT TUBERCULOSIS WITH DUAL THERAPY COMBINING PYRAZINAMIDE AND LEVOFLOXACIN. PEDIATR-INFECT-DIS-J.", "literaturereference_normalized": "drug induced fulminant hepatitis in a child treated for latent multidrug resistant tuberculosis with dual therapy combining pyrazinamide and levofloxacin", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200330", "receivedate": "20200330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17597176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "FR-MYLANLABS-2019M1123075", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "076276", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/KILOGRAM, QD (15 MG/KG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LATENT TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "25 MILLIGRAM/KILOGRAM, QD (25 MG/KG/DAY )", "drugenddate": null, "drugenddateformat": null, "drugindication": "LATENT TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "26", "reaction": [ { "reactionmeddrapt": "Cholestasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cell death", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HUGUET A, ADER F, OHLMANN C, COLLARDEAU-FRACHON S, GILLET Y.ET.AL.. DRUG-INDUCED FULMINANT HEPATITIS IN A CHILD TREATED FOR LATENT MULTIDRUG-RESISTANT TUBERCULOSIS WITH DUAL THERAPY COMBINING PYRAZINAMIDE AND LEVOFLOXACIN.. PEDIATR. INFECT. DIS. J.. 2019?38(10):1025-1026", "literaturereference_normalized": "drug induced fulminant hepatitis in a child treated for latent multidrug resistant tuberculosis with dual therapy combining pyrazinamide and levofloxacin", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200326", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17262232, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "FR-MICRO LABS LIMITED-ML2020-01156", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "205600", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "15 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "25 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "26", "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HUGUET A, ADER F, OHLMANN C, COLLARDEAU-FRACHON S, GILLET Y. DRUG-INDUCED FULMINANT HEPATITIS IN A CHILD TREATED FOR LATENT MULTIDRUG-RESISTANT TUBERCULOSIS WITH DUAL THERAPY COMBINING PYRAZINAMIDE AND LEVOFLOXACIN. PEDIATR-INFECT-DIS-J. 2019?38(10):1025-1026.", "literaturereference_normalized": "drug induced fulminant hepatitis in a child treated for latent multidrug resistant tuberculosis with dual therapy combining pyrazinamide and levofloxacin", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200410", "receivedate": "20200410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17655371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "Pulmonary air leak syndromes are extremely rare complications of systemic autoimmune connective tissue diseases and the occurrence of spontaneous subcutaneous emphysema (SSE) from pulmonary leak in the absence of pneumothorax or pneumomediastinum is even rarer. We report a case of recurrent SSE in a patient with rheumatoid arthritis and interstitial lung disease. The SSE was managed conservatively each time and it resorbed over several days. There has been no previous documented report of SSE in the absence of pneumomediastinum, pneumothorax or pulmonary nodules in a patient with RA.", "affiliations": "Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.;Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria.;Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.;Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.", "authors": "Adelowo\|Olufemi\|O\|;Akintayo\|Richard Oluyinka\|RO\|;Olaosebikan\|Hakeem\|H\|;Oba\|Rasheedat\|R\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D035583:Rare Diseases; D012008:Recurrence; D013352:Subcutaneous Emphysema; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26472288", "pubdate": "2015-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10091485;19916579;9267111;17764060;22767622;10858424;6375617;24761533;15729122;15026583;10784520;10092167;24231065;3343723;17136544;18311044", "title": "Recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis.", "title_normalized": "recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis" }	[ { "companynumb": "NG-PFIZER INC-2016393060", "fulfillexpeditecriteria": "1", "occurcountry": "NG", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "VITAMIN SUPPLEMENTATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "15 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary fibrosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ADELOWO, OLUFEMI. RECURRENT SPONTANEOUS SUBCUTANEOUS EMPHYSEMA IN A PATIENT WITH RHEUMATOID ARTHRITIS. BMJ CASE REPORTS. 2015", "literaturereference_normalized": "recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis", "qualification": "1", "reportercountry": "NG" }, "primarysourcecountry": "NG", "receiptdate": "20161122", "receivedate": "20160818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12665664, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "NG-ACCORD-043544", "fulfillexpeditecriteria": "1", "occurcountry": "NG", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VITAMIN SUPPLEMENTATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary fibrosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ADELOWO O, AKINTAYO RO, OLAOSEBIKAN H, OBA R. RECURRENT SPONTANEOUS SUBCUTANEOUS EMPHYSEMA IN A PATIENT WITH RHEUMATOID ARTHRITIS. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subcutaneous emphysema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ADELOWO, OLUFEMI. 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{ "abstract": "A 46-year-old female with no previous personal or family psychiatric history underwent endoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) to treat pain related to cystic fibrosis transmembrane conductance regulator-associated chronic pancreatitis. She had excellent response to her first three CPBs using bupivacaine and triamcinolone. The patient's subsequent CPBs were complicated by symptoms of racing thoughts, delusional thinking, and insomnia. She was diagnosed with acute psychosis secondary to triamcinolone. This is the first reported case of steroid-induced psychosis caused by EUS-guided CPB. Optimal treatment for steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroids and administration of lithium, valproic acid, or atypical antipsychotics.", "affiliations": "Department of Gastroenterology, Carolinas Medical Center, Charlotte, NC.;Department of Gastroenterology, Carolinas Medical Center, Charlotte, NC.", "authors": "Olson\|David C\|DC\|;Lewis\|Jason J\|JJ\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.14309/crj.2017.11", "fulltext": "\n==== Front\nACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.1110.14309/crj.2017.11Case ReportPancreasSteroid-Induced Psychosis after EUS-Guided Celiac Plexus Blockade Olson et alSteroid-Induced Psychosis Following EUS-Guided CPBOlson David C. MDLewis Jason J. MDDepartment of Gastroenterology, Carolinas Medical Center, Charlotte, NCCorrespondence: David C. Olson, Carolinas Medical Center, 1000 Blythe Blvd, MEB 5th Floor, Charlotte, NC 28210 (David.Olson@carolinas.org).2017 18 1 2017 4 e1112 8 2016 14 11 2016 Copyright © Olson et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/A 46-year-old female with no previous personal or family psychiatric history underwent endoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) to treat pain related to cystic fibrosis transmembrane conductance regulator-associated chronic pancreatitis. She had excellent response to her first three CPBs using bupivacaine and triamcinolone. The patient’s subsequent CPBs were complicated by symptoms of racing thoughts, delusional thinking, and insomnia. She was diagnosed with acute psychosis secondary to triamcinolone. This is the first reported case of steroid-induced psychosis caused by EUS-guided CPB. Optimal treatment for steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroids and administration of lithium, valproic acid, or atypical antipsychotics.\n==== Body\nIntroduction\nEndoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) and neurolysis were first described in 1996 and have since been shown to be effective procedures for the management of abdominal pain in the setting of chronic pancreatitis and pancreatic cancer, respectively.1,2 The most common complications following EUS-guided CPB include transient symptoms such as self-limited diarrhea and hypotension.3\n\nCase Report\nA 46-year-old woman with no previous personal or family psychiatric history underwent EUS-guided CPB to treat severe pain from chronic pancreatitis related to mutations in the cystic fibrosis transmembrane conductance regulator (CTFR) gene. In addition to opioid pain management, the patient underwent successful EUS-guided CPBs at 4-month intervals and had received 3 CPBs in the previous 13 months. Her procedures were performed via the standard transgastric approach. Color Doppler guidance was used to confirm a lack of significant vascular structures within the injection needle path, and needle aspiration was performed prior to injection to exclude entry into a blood vessel (Figure 1). A total of 20 mL 0.25% bupivacaine and 2 mL 40 mg/mL triamcinolone (80 mg) were injected in the area of the celiac plexus using a 20-gauge needle during each procedure (Figure 2).\n\nFigure 1 EUS image identifying the celiac axis with lack of significant vascular structures within the injection needle path.\n\nFigure 2 EUS image showing successful injection of triamcinolone/bupivacaine in the area of the celiac plexus.\n\nThe patient tolerated her first 3 procedures well and achieved excellent pain relief without any significant post-procedural complications. After her fourth EUS-guided CPB, the patient noticed racing thoughts for 2 weeks. These symptoms resolved spontaneously, and she did not share her symptoms with her treating physicians. After her next procedure, the patient began experiencing symptoms of mania, including racing thoughts, delusional thinking, pressured speech, extreme anger, and insomnia. She also developed severe depression and anxiety, with 1 episode of suicidal ideation. She was subsequently diagnosed with acute psychosis secondary to triamcinolone and newly diagnosed bipolar disorder. The patient was treated with clonazepam and lithium, with complete resolution of her symptoms after several weeks. Following multidisciplinary review, it was felt that the risk of recurrent psychosis following subsequent CPBs outweighed the potential benefit of any temporary pain relief the patient received. The patient subsequently underwent a total pancreatectomy and has had an uneventful medical and psychiatric post-operative course.\n\nDiscussion\nThis is the first reported case of acute steroid-induced psychosis caused by EUS-guided CPB. While steroid-induced psychosis after administration of systemic corticosteroids has been extensively reported since the introduction of corticosteroids in the early 1950s, psychosis from regional administration is much more rare.4 Episodes of acute psychosis following epidural, intramuscular, and intraarticular corticosteroid administration have been reported.5-7 To our knowledge, only two cases of acute psychosis following regional CPB have been reported.8 In both of these cases, the patients received an anesthesiologist-administered CPB with triamcinolone via a posterior approach under fluoroscopic guidance. Additionally, both patients also had a known history of steroid-induced psychosis from previous systemic corticosteroid administration.\n\nThe pathophysiology by which corticosteroids cause psychosis is not fully understood. Suppression of the hypothalamus-pituitary axis and enhanced dopamine neurotransmission has been postulated as a cause.9 Decreased hippocampal volume has been demonstrated in patients receiving chronic corticosteroid therapy for >6 months, leading some to suggest that the action of corticosteroids at steroid-specific receptors in the hippocampus results in a decreased ability to filter irrelevant stimuli.10,11 Risk factors for the development of steroid-induced psychosis are not known. A history of psychiatric illness and previous courses of corticosteroids had been hypothesized to increase risk, but both of these predictors appear to be unreliable.10 There are no reported associations between psychiatric disease or acute psychosis and the presence of CTFR mutations. Optimal treatment for patients presenting with steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroid therapy and administration of lithium, valproic acid, neuroleptics, or atypical antipsychotics.12 Most patients will have improvement of symptoms within 2 weeks of initiation of treatment.\n\nAs the patient in this case received a combination of corticosteroids and local anesthetic, it is important to note that local anesthetics have also been associated with psychological phenomena. Several cases of patients experiencing hallucinations following administration of lidocaine, procainamide, bupivacaine, mepivacaine, and procaine for the purpose of regional anesthesia, pain relief, or management of ectopies have been reported.13 However, the majority of these patients experienced vivid fear of imminent death or delusional beliefs of having died rather than overt psychosis.\n\nIt is important for endoscopists to be aware of the potential adverse side effects associated with steroid administration following EUS-guided CPB. While steroid-induced psychosis from EUS-guided CPB appears to be a rare entity, prompt recognition and treatment will help prevent further complications from untreated symptoms and repeated steroid administrations.\n\nDisclosures\nAuthor contributions: DC Olson wrote and revised the manuscript. JJ Lewis edited the manuscript and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1. Wiersema MJ , Wiersema LM \nEndosonography-guided celiac plexus neurolysis . Gastrointest Endosc . 1996 ;\n44 :656 –62 .8979053 \n2. Kaufman M , Singh G , Das S , et al \nEfficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer . J Clin Gastroenterol . 2010 ;\n44 :127 –34 .19826273 \n3. Fabbri C , Luigiano C , Lisotti A , et al \nEndoscopic ultrasound-guided treatments: Are we getting evidence based - a systematic review . World J Gastroentero . 2014 ;\n20 (26 ):8424 –48 .\n4. Hall RC , Popkin MK , Stickney SK , et al \nPresentation of the steroid psychoses . J Nerv Ment Dis . 1979 ;\n167 :229 –36 .438794 \n5. Benyamin RM , Vallejo R , Kramer J , et al \nCorticosteroid induced psychosis in the pain management setting . Pain Physician . 2008 ;\n11 (6 ):917 –20 .19057637 \n6. Teuber I , Freiwald D , Volz HP \nAcute paranoid symptoms following intramuscular injection of nandrolone . Psychiatr Prax . 2003 ;\n30 (Suppl 2 ):73 –4 .13130341 \n7. Robinson DE , Harrison-Hansley E , Spencer RF \nSteroid psychosis after an intra-articular injection . Ann Rheum Dis . 2000 ;\n59 (11 ):927 .\n8. Fishman SM , Catarau EM , Sachs G , et al \nCorticosteroid-induced mania after single regional application at the celiac plexus . Anesthesiology . 1996 ;\n85 :1194 –6 .8916839 \n9. Schatzberg AF , Rothschild AJ , Langlais PJ , et al \nA corticosteroid/dopamine hypothesis for psychotic depression and related states . J Psychiatr Res . 1985 ;\n19 (1 ):57 –64 .2859366 \n10. Naber D , Sand P , Heigl B \nPsychopathological and neuropsychological effects of 8-days' corticosteroid treatment. A prospective study . Psychoneuroendocrinology . 1996 ;\n21 (1 ):25 –31 .8778901 \n11. Brown ES , J Woolston D , Frol A , et al \nHippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy . Biol Psychiatry . 2004 ;\n55 (5 ):538 –45 .15023583 \n12. Brown ES , Chandler PA \nMood and cognitive changes during systemic corticosteroid therapy . Prim Care Companion J Clin Psychiatry . 2001 ;\n3 :17 –21 .15014624 \n13. Marsch SC , Schaefer HG , Castelli I \nUnusual psychological manifestation of systemic local anesthetic toxicity . Anesthesiology . 1998 ;\n88 (2 ):531 –3 .9477077\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2326-3253", "issue": "4()", "journal": "ACG case reports journal", "keywords": null, "medline_ta": "ACG Case Rep J", "mesh_terms": null, "nlm_unique_id": "101638398", "other_id": null, "pages": "e11", "pmc": null, "pmid": "28144616", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "2859366;8778901;15014624;438794;9477077;13130341;25024600;8916839;19057637;15023583;8979053;11203422;19826273", "title": "Steroid-Induced Psychosis after EUS-Guided Celiac Plexus Blockade.", "title_normalized": "steroid induced psychosis after eus guided celiac plexus blockade" }	[ { "companynumb": "US-PFIZER INC-2017085973", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "80 MG (2 ML 40 MG/ML)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPIVACAINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "016964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "20 ML, UNK (0.25% BUPIVACAINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE HCL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bipolar disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON, D.. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG CASE REPORTS JOURNAL. 2017?4 (2):1-3", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180104", "receivedate": "20170322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13360188, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" }, { "companynumb": "US-MYLANLABS-2017M1031984", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 ML 0.25%", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRIAMCINOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "011601", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2 ML 40 MG/ML TRIAMCINOLONE (80 MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute psychosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON DC, LEWIS JJ. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG-CASE-REP-J 2017;4(2):1-3.", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170526", "receivedate": "20170526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13587355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-AKORN PHARMACEUTICALS-2017AKN00750", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "202374", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "80 MG, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NERVE BLOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 ML, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NERVE BLOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Substance-induced psychotic disorder", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON D, LEWISH J. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG CASE REP J (DOI 10.14309/CRJ.2017.11). 2017;4(2):ARTICLE #1-3, E11", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170613", "receivedate": "20170613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13647323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK026558", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 ML 40 MG/ML TRIAMCINOLONE (80 MG), EUS-GUIDED CPBS AT 4-MONTH INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 ML, EUS-GUIDED CPBS AT 4-MONTH INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON DC, LEWIS JJ. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG CASE REP J.. 2017;4:E11", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170302", "receivedate": "20170302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13288263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "Salivary duct carcinoma is a malignant salivary neoplasm with a poor prognosis. Effective treatment for remote metastases has not been recognized. We report herein on a case of this tumor overexpressing HER2 successfully treated with trastuzumab-based molecular targeted therapy. The patient was a 69-year-old man, who developed remote metastases into the liver and the thoracic vertebra six months after surgery and postoperative irradiation for the primary and nodal lesions. After targeted therapy including paclitaxel and trastuzumab, these metastatic lesions showed rapid and continued regression. After paclitaxel was discontinued due to peripheral neuropathy in the extremities, trastuzumab monotherapy followed without resulting in cardiotoxicity. After three years since development of remote metastases, the patient is doing well without re-progression of the disease.", "affiliations": null, "authors": "Iguchi\|Fukuichiro\|F\|;Taniguchi\|Zenchi\|Z\|;Kusano\|Junko\|J\|;Takahashi\|Yuka\|Y\|;Murai\|Norihiko\|N\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000068878:Trastuzumab; D017239:Paclitaxel", "country": "Japan", "delete": false, "doi": "10.3950/jibiinkoka.117.1108", "fulltext": null, "fulltext_license": null, "issn_linking": "0030-6622", "issue": "117(8)", "journal": "Nihon Jibiinkoka Gakkai kaiho", "keywords": null, "medline_ta": "Nihon Jibiinkoka Gakkai Kaiho", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D044584:Carcinoma, Ductal; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D018987:Salivary Ducts; D012468:Salivary Gland Neoplasms; D000068878:Trastuzumab", "nlm_unique_id": "7505728", "other_id": null, "pages": "1108-14", "pmc": null, "pmid": "25255650", "pubdate": "2014-08", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of metastatic salivary duct carcinoma successfully treated with trastuzumab-based targeted therapy.", "title_normalized": "a case of metastatic salivary duct carcinoma successfully treated with trastuzumab based targeted therapy" }	[ { "companynumb": "JP-ACCORD-026416", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "075436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2 ON DAY 1, 8, AND 15.?THEN 50 MG/M2 ONCE A WEEK.", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201010", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCALCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201010", "drugstartdateformat": "610", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201209" } }, "primarysource": { "literaturereference": "IGUCHI F, TANIGUCHI Z, KUSANO J, TAKAHASHI Y, MURAI N. [A CASE OF METASTATIC SALIVARY DUCT CARCINOMA SUCCESSFULLY TREATED WITH TRASTUZUMAB-BASED TARGETED THERAPY]. NIHON JIBIINKOKA GAKKAI KAIHO. 2014 AUG;117(8):1108-14.", "literaturereference_normalized": "a case of metastatic salivary duct carcinoma successfully treated with trastuzumab based targeted therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141030", "receivedate": "20141030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10553778, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]
{ "abstract": "BACKGROUND\nEncephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10-30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA).\n\n\nMETHODS\nThis is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms.\n\n\nCONCLUSIONS\nThe rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.", "affiliations": "Department of Medical Oncology, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. juliette.hamilton@gmail.com.;Department of Neurophysiology, Tallaght University Hospital, Dublin, Ireland.;Department of Medical Oncology, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.", "authors": "Hamilton\|Juliette E\|JE\|http://orcid.org/0000-0002-9614-6500;Alexander\|Michael\|M\|;Kelleher\|Fergal C\|FC\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13569-020-00147-3", "fulltext": "\n==== Front\nClin Sarcoma Res\nClin Sarcoma Res\nClinical Sarcoma Research\n2045-3329 BioMed Central London \n\n147\n10.1186/s13569-020-00147-3\nCase Report\nIfosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report\nhttp://orcid.org/0000-0002-9614-6500Hamilton Juliette E. juliette.hamilton@gmail.com 1 Alexander Michael 2 Kelleher Fergal C. 1 1 Department of Medical Oncology, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland \n2 Department of Neurophysiology, Tallaght University Hospital, Dublin, Ireland \n28 11 2020 \n28 11 2020 \n2020 \n10 255 7 2020 20 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nEncephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10–30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA).\n\nCase presentation\nThis is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms.\n\nConclusion\nThe rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.\n\nKeywords\nIfosfamide Encephalopathy Methylene blue Frontal rhythmic intermittent delta activity FIRDAissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIfosfamide (3-[2-chloroethyl]-2-[(2-chloroethyl)-amino] tetrahydro-2H-1, 3,2-oxazaphosphorin-2-oxide) is a chemotherapeutic agent used for a variety of solid organ and haematological malignancies, including in the management of sarcomas [1, 2]. It is a prodrug that is metabolized in the liver into the active alkylating agents by cytochrome P450 enzymes [3]. The alkylating agents produced are 4-hydroxy-ifosfamide and ifosfamide mustard with other resultant products including chloroacetaldehyde and chlorothylamine. Chloroacetaldehyde and chlorothylamine are thought likely to be the major contributing factors in the development of encephalopathy, as they are known to be neurotoxic and are able to penetrate the blood–brain barrier [3, 4]. These metabolites are excreted predominantly by the kidneys [2].\n\nNeurotoxicity can manifest in several ways, including lethargy, agitation, disorientation, confusion, hallucinations, extra-pyramidal signs and seizures [1, 5]. In rare cases, the symptoms can progress to coma, irreversible brain damage and death [1]. These symptoms are thought to develop due to glutaric acid accumulation, which may inhibit mitochondrial respiration [4]. This specific pathway was identified after glutaric acid was found in the urine of patients with congenital glutaric aciduria, a congenital metabolic disorder which results in a lack of the flavoproteins for electron transfer in mitochondrial respiration [6]. This disturbance leads to an increase in intracellular nicotinamide adenine dinucleotide, inhibiting the dehydrogenation and oxidation of chloroacetaldehyde and chlorothylamine [3].\n\nThere are many hypothesised risk factors for the development of ifosfamide-induced encephalopathy. Advanced age, poor performance status, impaired renal and liver function, past history of intracerebral pathology, platinum exposure, malnutrition evidenced by low albumin, higher levels of haemoglobin, concomitant use of aprepitant and lower gastrointestinal and pelvic malignancies [3, 7]. Aprepitant is a CYP 3A4 enzyme inhibitor, and therefore has the potential to increase the levels of chloroacetaldehyde and chlorothylamine [1].\n\nIfosfamide-induced encephalopathy is a clinical diagnosis, with onset within 2 h up to 146 h after the commencement of the ifosfamide infusion [1]. It is graded by severity, with grade 1 encompassing a vague or slightly depressive affect, grade 2 resulting in extensive periods of sleep, restlessness or agitation, grade 3 manifests as stupor, heavy depression or mild hallucinations and grade 4 expressing overt hallucinations, seizures or coma [2, 3].\n\nResolution of symptoms have been observed with the administration of methylene blue. Whilst the exact mechanism of action is unclear, it is felt that it serves as an alternative electron acceptor. This prevents chlorothylamine from inhibiting flavoprotein and so corrects mitochondrial respiration [1]. It also inhibits extra-hepatic monoamine oxidases, preventing the dehydrogenation of aldehydes, including the formation of chloroacetaldehyde [1, 2, 6]. The toxicities of methylene blue include cardiac arrhythmias, coronary vasoconstriction, syncope, hemolytic anemia and anaphylaxis [8].\n\nThiamine has also been used in the management of ifosfamide-induced encephalopathy, specifically because of the similar clinical syndrome of Wernicke’s encephalopathy, and has been found to be effective [2]. Additionally, albumin administration to provide binding sites that are unable to cross the blood brain barrier, and haemodialysis, have been found to be effective [2].\n\nCase presentation\n\nOur patient was a 71 year old woman diagnosed with a high-grade right triceps pleomorphic sarcoma in 2017, which was resected with a wide local excision and treated with adjuvant radiation. A surveillance computed tomography (CT) scan of the thorax showed metastases to the lung and mediastinum in September 2018 and she was treated with 6 cycles of doxorubicin. Progression of disease identified in January 2019 necessitated a change of treatment to ifosfamide and mesna, and she was admitted for each cycle. Re-staging CT scan after 2 cycles demonstrated an interval decrease in the size and number of the multiple pulmonary nodules with one nodule reducing in size from 18 mm down to 6 mm, complete resolution of a 15 mm right para-oesophageal node and no new disease identified.\n\nPast medical history included hypertension, hysterectomy for menorrhagia and appendectomy. Her medications on admission were lercanidipine, losartan, hydrochlorothiazide, potassium supplement, enoxaparin (thrombosis prophylaxis), senna, domperidone, aprepitant, Fortisip Compact Fibre, Procal Shot, multivitamin and evening primrose oil (not administered due to unknown possible drug interactions). She was known to develop a rash with penicillin but had no other allergies.\n\nExamination on admission for cycle 3 was remarkable for oral candidiasis. Routine blood investigations identified potassium 2.7 mmol/l which was replaced with IV and oral potassium and albumin of 32 g/l. She developed nausea after day 2 and had one episode of vomiting.\n\nOn day 3, she was noted to be resting during the morning, however was easily rousable and able to stay awake. Chemotherapy was commenced at midday. Within 4 h, it was noted that she was difficult to rouse. Vital signs were within normal ranges. A blood gas confirmed a potassium of 2.7 mmol/l, but no other abnormality was identified and the pH was uncompensated and in the normal range. An ECG was unremarkable. It was hypothesized that she had developed ifosfamide encephalopathy and an EEG was obtained.\n\nDiscussion\nIn the EEG (Fig. 1) taken while the patient was encephalopathic, one can see the generalized features of periodic discharges, occasional triphasic morphology and intermittent delta activity with background attenuation. In addition to this, there is rhythmic delta activity seen intermittently. Unusually, this EEG demonstrates the unusual and rare finding of frontal intermittent rhythmic delta activity (FIRDA) [9]. FIRDA is a non-specific finding associated with frontal pathologies and has been descried in severe metabolic encephalopathies and in cases with significant mid-line shifts. This is a rarely seen phenomenon and was only identified in one case of a recent study by Gudson et al. [10].Fig. 1 The EEG demonstrating FIRDA\n\n\n\nMethylene blue, 50 mg intravenous (IV) slow push, was administered and there was a remarkable recovery with resolution of the drowsiness within 10 min of administration. On resolution of symptoms, the patient reported that she felt considerably better and that she was aware that she had been drowsy and unable to appropriately rouse herself. Oral thiamine was administered and the patient was admitted to the intensive care unit for monitoring. A further EEG was performed after resolution of symptoms, and all the previous features of encephalopathy were proven to have resolved.\n\nLikely contributing factors to the ifosfamide-induced encephalopathy seen in this patient were her advanced age, low albumin, renal impairment manifesting in deranged electrolytes and the addition of aprepitant to her regimen.\n\nConclusions\nThis case is interesting as it adds to evidence to benefit of methylene blue in the management of ifosfamide-induced encephalopathy, and also demonstrates the rarely observed EEG phenomenon of FIRDA during the ifosfamide-induced encephalopathy.\n\nAbbreviations\nCTComputed tomography\n\nEEGElectroencephalogram\n\nFIRDAFrontal rhythmic intermittent delta activity\n\nIVIntravenous\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors' contributions\nJH wrote the paper. MA provided the EEG that was on record from the event and the commentary on the EEG’s. FK provided guidance on the structure of case and reviewed the final submission. All authors read and approved the final manuscript.\n\nFunding\nNo funding was sought or obtained.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent for publication of all information was obtained in writing from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Richards A Marshall H McQuary A Evaluation of methylene blue, thiamine, and/or albumin in the prevention of ifosfamide-related neurotoxicity J Oncol Pharm Pract 2011 17 4 372 80 10.1177/1078155210385159 20861178 \n2. Kataria PS Kendre PP Patel AA Ifosfamide-induced Encephalopathy Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction J Pharmacol Pharmacother 2017 8 1 38 40 10.4103/jpp.JPP_182_16 28405136 \n3. Liu YL Tsai SH Chang FW Yu MH Ifosfamide-induced encephalopathy in patients with uterine sarcoma Taiwan J Obstet Gynecol 2010 49 1 77 80 10.1016/S1028-4559(10)60014-9 20466298 \n4. Sejourne A Noal S Boone M Bihan C Sassier M Andrejak M Two cases of fatal encephalopathy related to ifosfamide: an adverse role of aprepitant? Case Rep Oncol 2014 7 3 669 72 10.1159/000368184 25408661 \n5. Lo Y Shen LJ Chen WH Dong YH Wu FL Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: a retrospective analysis J Formos Med Assoc 2016 115 9 744 51 10.1016/j.jfma.2015.07.016 26302952 \n6. Pelgrims J De Vos F Van den Brande J Schrijvers D Prove A Vermorken JB Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature Br J Cancer 2000 82 2 291 4 10.1054/bjoc.1999.0917 10646879 \n7. Gharaibeh EZ Telfah M Powers BC Salacz ME Hydration, methylene blue, and thiamine as a prevention regimen for ifosfamide-induced encephalopathy J Oncol Pharm Pract 2019 25 7 1784 6 10.1177/1078155218808361 30348070 \n8. Ginimuge PR Jyothi SD Methylene blue: revisited J Anaesthesiol Clin Pharmacol 2010 180 4 517 20 \n9. Dericioglu N Khasiyev F Arsava EM Topcuoglu MA Frontal Intermittent Rhythmic Delta Activity (FIRDA) in the neurological intensive care: prevalence, determinants, and clinical significance Clin EEG Neurosci 2018 49 4 272 7 10.1177/1550059416688108 28118746 \n10. Gudson AMMR Chen X Clinical and EEG characteristics of ifosfamide-related encephalopathy J Clin Neurophysiol 2019 36 2 150 4 10.1097/WNP.0000000000000539 30694943\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-3329", "issue": "10(1)", "journal": "Clinical sarcoma research", "keywords": "Encephalopathy; Frontal rhythmic intermittent delta activity FIRDA; Ifosfamide; Methylene blue", "medline_ta": "Clin Sarcoma Res", "mesh_terms": null, "nlm_unique_id": "101577890", "other_id": null, "pages": "25", "pmc": null, "pmid": "33292592", "pubdate": "2020-11-28", "publication_types": "D016428:Journal Article", "references": "20861178;21547182;25408661;28118746;30694943;28405136;26302952;30348070;20466298;10646879", "title": "Ifosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report.", "title_normalized": "ifosfamide induced encephalopathy the eeg with frontal intermittent delta activity and rapid 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOMPERIDONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SENNA LEAF\\SENNOSIDES\\SENNOSIDES A AND B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SENNA" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAMILTON JE, ALEXANDER M, KELLEHER FC. IFOSFAMIDE?INDUCED ENCEPHALOPATHY: THE EEG WITH FRONTAL INTERMITTENT DELTA ACTIVITY, AND RAPID RESOLUTION WITH METHYLENE BLUE: A CASE REPORT. 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IFOSFAMIDE INDUCED ENCEPHALOPATHY: THE EEG WITH FRONTAL INTERMITTENT DELTA ACTIVITY, AND RAPID RESOLUTION WITH METHYLENE BLUE: A CASE REPORT. 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IFOSFAMIDE?INDUCED ENCEPHALOPATHY: THE EEG WITH FRONTAL INTERMITTENT DELTA ACTIVITY, AND RAPID RESOLUTION WITH METHYLENE BLUE: A CASE REPORT. CLIN SARCOMA RES. 2020?10(1)", "literaturereference_normalized": "ifosfamide induced encephalopathy the eeg with frontal intermittent delta activity and rapid resolution with methylene blue a case report", "qualification": "3", "reportercountry": "IE" }, "primarysourcecountry": "IE", "receiptdate": "20210315", "receivedate": "20210315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19009935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients.", "affiliations": "Internal Medicine Department, University of São Paulo State, São Paulo, Brazil.", "authors": "Neves\|Precil Diego M M\|PD\|;Freitas\|Fernanda M\|FM\|;Kojima\|Christiane A\|CA\|;Carmello\|Beatriz L\|BL\|;Bazan\|Rodrigo\|R\|;Barretti\|Pasqual\|P\|;Martin\|Luis C\|LC\|", "chemical_list": "D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin", "country": "Canada", "delete": false, "doi": "10.1111/hdi.12194", "fulltext": null, "fulltext_license": null, "issn_linking": "1492-7535", "issue": "19(1)", "journal": "Hemodialysis international. International Symposium on Home Hemodialysis", "keywords": "Chronic kidney disease; hemodialysis; neurotoxicity; piperacillin/tazobactam", "medline_ta": "Hemodial Int", "mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic", "nlm_unique_id": "101093910", "other_id": null, "pages": "143-5", "pmc": null, "pmid": "25098503", "pubdate": "2015-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: a case report.", "title_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report" }	[ { "companynumb": "PHHY2015BR015290", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "065362", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN AND TAZOBACTAM" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebellar syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "VIIth nerve paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NEVES PD MM, FREITAS FM, KOJIMA CA, CARMELLO BL, BAZAN R, BARRETTI P, ET AL.. PIPERACILLIN/TAZOBACTAM-INDUCED NEUROTOXICITY IN A HEMODIALYSIS PATIENT: A CASE REPORT.. HEMODIAL-INT. 2015;19(1):143-5", "literaturereference_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150210", "receivedate": "20150210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10779957, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "BR-MYLANLABS-2015M1004453", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "065458", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G/250 MG IN EVERY 6 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN/TAZOBACTAM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFEPIME HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G AFTER EACH HAEMODIALYSIS SESSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEPECEF" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemodialysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NEVES PDMM, FREITAS FM, KOJIMA CA, CARMELLO BL, BAZAN R, BARRETTI P, ET AL. PIPERACILLIN/TAZOBACTAM-INDUCED NEUROTOXICITY IN A HEMODIALYSIS PATIENT: A CASE REPORT. HEMODIAL-INT 2015; 19(1):143-145.", "literaturereference_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150216", "receivedate": "20150216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10797542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "BR-PFIZER INC-2015167292", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050684", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2G/250MG, 4X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN/TAZOBACTAM" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebellar syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cranial nerve paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NEVES, P.D.M.M.. PIPERACILLIN/TAZOBACTAM-INDUCED NEUROTOXICITY IN A HEMODIALYSIS PATIENT: A CASE REPORT. HEMODIALYSIS INTERNATIONAL. 2015;19 (1):143-145", "literaturereference_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11125170, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.\n\n\n\nThe extent of identified changes in CLL cells versus memory B cells from healthy donors was termed \"epigenetic burden\" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed \"relapse changes\" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.\n\n\n\nOverall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.", "affiliations": "Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.;Department of Biology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.;Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.;Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.;Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece. kostas.stamatopoulos@gmail.com.", "authors": "Tsagiopoulou\|Maria\|M\|;Papakonstantinou\|Nikos\|N\|;Moysiadis\|Theodoros\|T\|;Mansouri\|Larry\|L\|;Ljungström\|Viktor\|V\|;Duran-Ferrer\|Martí\|M\|;Malousi\|Andigoni\|A\|;Queirós\|Ana C\|AC\|;Plevova\|Karla\|K\|;Bhoi\|Sujata\|S\|;Kollia\|Panagoula\|P\|;Oscier\|David\|D\|;Anagnostopoulos\|Achilles\|A\|;Trentin\|Livio\|L\|;Ritgen\|Matthias\|M\|;Pospisilova\|Sarka\|S\|;Stavroyianni\|Niki\|N\|;Ghia\|Paolo\|P\|;Martin-Subero\|Jose I\|JI\|;Pott\|Christiane\|C\|;Rosenquist\|Richard\|R\|;Stamatopoulos\|Kostas\|K\|0000-0001-8529-640X", "chemical_list": "D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine", "country": "Germany", "delete": false, "doi": "10.1186/s13148-019-0783-1", "fulltext": "\n==== Front\nClin EpigeneticsClin EpigeneticsClinical Epigenetics1868-70751868-7083BioMed Central London 78310.1186/s13148-019-0783-1ResearchDNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy Tsagiopoulou Maria 12Papakonstantinou Nikos 1Moysiadis Theodoros 13Mansouri Larry 34Ljungström Viktor 4Duran-Ferrer Martí 5Malousi Andigoni 6Queirós Ana C. 5Plevova Karla 78Bhoi Sujata 4Kollia Panagoula 2Oscier David 9Anagnostopoulos Achilles 10Trentin Livio 11Ritgen Matthias 12Pospisilova Sarka 78Stavroyianni Niki 10Ghia Paolo 13Martin-Subero Jose I. 514Pott Christiane 12Rosenquist Richard 3http://orcid.org/0000-0001-8529-640XStamatopoulos Kostas kostas.stamatopoulos@gmail.com 131 Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001 Thermi, Thessaloniki, GR Greece 2 0000 0001 2155 0800grid.5216.0Department of Biology, National and Kapodistrian University of Athens, Athens, Greece 3 0000 0004 1937 0626grid.4714.6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 4 0000 0004 1936 9457grid.8993.bDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 0000 0004 1937 0247grid.5841.8Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain 6 0000000109457005grid.4793.9Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece 7 0000 0004 0609 2751grid.412554.3Department of Internal Medicine–Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic 8 0000 0001 2194 0956grid.10267.32Central European Institute of Technology, Masaryk University, Brno, Czech Republic 9 0000 0000 9910 8169grid.416098.2Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK 10 0000 0004 0576 574Xgrid.415248.eHematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece 11 0000 0004 1757 3470grid.5608.bDepartment of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy 12 0000 0004 0646 2097grid.412468.dSecond Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 13 0000000417581884grid.18887.3eDivision of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy 14 0000 0000 9601 989Xgrid.425902.8Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 2 12 2019 2 12 2019 2019 11 17724 9 2019 19 11 2019 © The Author(s). 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.\n\nResults\nThe extent of identified changes in CLL cells versus memory B cells from healthy donors was termed “epigenetic burden” (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed “relapse changes” (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.\n\nConclusions\nOverall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.\n\nKeywords\nDNA methylationChemoimmunotherapyCLLMicroarray analysisRelapsehttp://dx.doi.org/10.13039/100008594European Hematology Associationhttp://dx.doi.org/10.13039/501100005010Associazione Italiana per la Ricerca sul Cancro21198http://dx.doi.org/10.13039/501100001823Ministerstvo Školství, Mládeže a TělovýchovyCEITEC2020 LQ1601http://dx.doi.org/10.13039/501100007601Horizon 2020AEGLEGeneral Secretatiat for research and technology of GreeceKRIPISERA-NET TRANSCAN-2 JTC 2014, GCH-CLL143MIUR-PRIN2015ZMRFEASwedish Cancer SocietySwedish Cancer SocietyKnut och Alice Wallenbergs Stiftelse (SE)Knut och Alice Wallenbergs Stiftelse (SE)Swedish Research CouncilSwedish Research Councilhttp://dx.doi.org/10.13039/501100007232Radiumhemmets ForskningsfonderRadiumhemmets ForskningsfonderLion’s Cancer Research FoundationLion’s Cancer Research FoundationMarcus Borgström’s FoundatioMarcus Borgström’s FoundatioSelander’s FoundationSelander’s FoundationState of scholarships foundation of GreecefellowshipTsagiopoulou Maria issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMounting evidence highlights a significant contribution of DNA methylation in the onset and evolution of CLL [1]. To large extent, the CLL methylome shares common features with the normal B cell differentiation program [2, 3]. As a whole, CLL cells resemble memory B cells, exhibiting great similarity with the DNA methylation programming for high-maturity memory B cells [3]. Against the initial view that the DNA methylome remains relatively stable, more recent evidence indicates that DNA methylation may evolve overtime, also with respect to treatment [2, 4, 5]. Indeed, patients with mutated IGHV genes (M-CLL) who experience stable disease also display stable DNA methylation patterns overtime, along with limited genetic changes [2]. In contrast, patients with unmutated IGHV genes (U-CLL) appear to show a more wide variation in DNA methylation changes over time [2, 4] along with the appearance of subclones with different genetic aberrations [4]. Despite this evidence, however, the epigenomic contribution to CLL progression remains to be conclusively defined.\n\nThe fludarabine-cyclophosphamide-rituximab (FCR) regimen is a standard treatment option for medically fit CLL patients, excepting those who carry aberrations of the TP53 gene [mutation and/or del(17p)] [6–9]. In fact, along with the somatic hypermutation status of the clonotypic IGHV genes, they are the main predictors of response to FCR treatment in CLL [7–9]. Although FCR is effective with overall response rates in the range of 90%, most patients will eventually relapse with those relapsing within 2 years after FCR experiencing a particularly aggressive disease (“ultra high risk”) [10, 11]. These observations point to a characteristic resistance of the malignant cells that is still not fully characterized from the epigenetic perspective and cannot be reliably predicted, at least for cases not falling in any of the risk categories defined by genetic or immunogenetic biomarkers.\n\nIn the present study, we analyzed the DNA methylomes in longitudinal pre-treatment and post-relapse samples of 34 CLL patients treated with chemoimmunotherapy in order to address if changes occur overtime in relation to therapy. We report that DNA methylation profiles are modulated during CLL evolution, particularly in response to treatment, involving several transcription factors and displaying association with particular genetic aberrations. Moreover, we evaluated the DNA methylation alterations occuring during neoplastic expansion, the so-called “epigenetic burden,” comparing the pre-treatment profiles per case with those of memory B cells from healthy donors and highlight that the EB clusters in specific genomic regions and chromatin states, including regulatory regions contaning binding sites of transcription factors implicated in B cell and CLL biology.\n\nResults\nGenome-wide profiling reveals significant heterogeneity of DNA methylation evolution in CLL\nWe assessed 68 paired samples from 34 CLL cases who received chemoimmunotherapy as first-line treatment: Of these, 31 were treated with the FCR regimen whereas one each of the remaining 3 cases received FC (fludarabine-cyclophosphamide), FCMR (fludarabine-cyclophosphamide-rituximab+mitoxantrone), or BR (bendamustine-rituximab) (Additional file 1: Table S1). Data from 20/34 pre-treatment CLL samples have been previously reported by our group [12]. The time-span between the two examined states (pre-treatment/post-relapse) ranged from 0.75 to 10.9 years with a median of 2.5 years (Table 1). The vast majority of cases concerned U-CLL (29/34, 85.2%), which are associated with adverse prognosis and significantly higher incidence of progressive disease requiring treatment. First, we performed unsupervised hierarchical clustering based on the methylation levels of 451,756 CpG sites across all samples: This analysis did not discriminate the pre-treatment samples from the post-relapse ones (Additional file 2: Figure S1). Next, we performed differential methylation analysis (DMA) at cohort level (\|db\| ≥ 0.3, p < 0.05 or \|db\| ≥ 0.3, FDR < 0.05), comparing all the pre-treatment versus all the post-relapse samples, again not identifying differentially methylated CpG (DMCpG) sites.\nTable 1 Clinical data and results of the intra-individual DNA methylation analysis\n\nPatient ID\tU-CLL\tIGHV gene\tAge at diagnosis\tFirst-line treatment\tTreatment response\tTTFT\tTTR\tCytogenetic alterations\tPearson R\n(MBC vs pre-treatment)\tEpigenetic burden\tPearson R\n(pre-treatment vs relapse)\tRelapse changes\t\nP1\tNO\tIGHV3-11\t48\tFCR\tPR\t1.6\t4.7\tNone\t0.93\t32,380\t0.99\t117\t\nP2\tND\tIGHV1-f\t61\tFCR\tCR\t1.1\t2.6\tdel(13q)\t0.92\t33,441\t0.96\t20,440\t\nP3\tYES\tIGHV3-33\t55\tFCR\tCR\t0.1\t2.3\tNone\t0.93\t34,285\t0.82\t81,383\t\nP4\tYES\tIGHV1-69\t60\tFCR\tCR\t4.3\t5.5\tTrisomy 12\t0.93\t35,098\t0.98\t8052\t\nP5\tYES\tIGVH1-69\t60\tFCR\tPR\t1.4\t1.4\tdel(13q)\t0.92\t36,696\t0.98\t3430\t\nP6\tYES\tIGHV3-33\t52\tFCR\tCR\t4.1\t6.4\tdel(13q)\t0.92\t37,146\t0.99\t3441\t\nP7\tYES\tIGHV4-39\t62\tFCR\tCR\t2.2\t3.6\tdel(11q), del(13q)\t0.92\t37,465\t0.89\t58,299\t\nP8\tYES\tIGHV1-69\t46\tFCR\tPR\t0.3\t1.7\tdel(11q)\t0.92\t38,023\t0.99\t1514\t\nP9\tYES\tIGHV4-31\t64\tFCR\tCR\t4.1\t3.8\tNone\t0.91\t38,652\t0.92\t40,706\t\nP10\tYES\tIGHV1-69\t61\tFCR\tCR\t1.2\t2.2\tdel(11q)\t0.91\t39,164\t0.97\t8199\t\nP11\tYES\tND\t56\tBR\tCR\t2\t3.9\tdel(13q)\t0.92\t39,658\t1.00\t45\t\nP12\tYES\tIGHV5-a\t73\tFCR\tCR\t0.2\t3.8\tND\t0.92\t40,403\t0.87\t60,970\t\nP13\tYES\tIGHV3-20\t49\tFCΜR\tPR\t2.5\t4.1\tTrisomy 12\t0.91\t40,669\t0.99\t511\t\nP14\tYES\tND\t29\tFCR\tPR\t1.5\t4.8\tdel(11q), del(13q)\t0.91\t40,755\t0.99\t1263\t\nP15\tYES\tIGHV1-69\t66\tFCR\tCR\t3.4\t0.9\tdel(11q), del(13q)\t0.91\t41,333\t0.99\t261\t\nP16\tYES\tIGHV4-34\t44\tFCR\tCR\t2.7\t1.4\tdel(11q)\t0.91\t41,399\t0.99\t392\t\nP17\tYES\tND\t36\tFCR\tCR\t2.2\t5.0\tNone\t0.90\t41,875\t0.98\t3150\t\nP18\tYES\tIGHV3-64\t26\tFCR\tCR\t0.9\t1.3\tdel(17p)\t0.91\t42,313\t0.99\t949\t\nP19\tNO\tIGHV1-69\t48\tFCR\tCR\t6.1\t1.8\tdel(13q)\t0.92\t42,384\t1.00\t45\t\nP20\tYES\tIGHV1-69\t61\tFCR\tND\t0\t1.1\tdel(6q)\t0.91\t42,543\t0.99\t457\t\nP21\tYES\tIGHV1-24\t59\tFCR\tCR\t0\t1.2\tNone\t0.91\t42,615\t0.99\t907\t\nP22\tYES\tIGHV3-30\t56\tFCR\tCR\t0\t0.8\tdel(11q)\t0.91\t42,721\t0.99\t287\t\nP23\tYES\tIGHV1-69\t54\tFCR\tCR\t1.5\t0.9\tdel(11q), del(13q)\t0.90\t44,283\t0.99\t90\t\nP24\tNO\tIGHV1-69\tND\tFCR\tCR\t4.7\t1.2\tdel(11q , del(13q)\t0.91\t45,253\t1.00\t45\t\nP25\tYES\tIGHV3-48\t65\tFCR\tCR\t2\t8.0\tdel(13q)\t0.91\t45,372\t0.99\t905\t\nP26\tYES\tIGHV1-69\t64\tFCR\tCR\t0.1\t2.2\tdel(11q)\t0.89\t45,383\t0.98\t4689\t\nP27\tND\tIGHV3-53\t43\tFCR\tCR\t0.1\t10.9\tTrisomy 12\t0.89\t45,999\t0.96\t10,449\t\nP28\tYES\tIGVH3B\t61\tFCR\tCR\t0.1\t1.4\tdel(17p)\t0.90\t46,314\t0.89\t51,925\t\nP29\tYES\tIGHV4-34\t53\tFCR\tCR\t0\t7.9\tNone\t0.90\t50,072\t0.98\t8546\t\nP30\tYES\tND\t55\tFC\tCR\t2\t3.0\tdel(11q)\t0.89\t50,443\t0.98\t2740\t\nP31\tYES\tIGVH3B\t50\tFCR\tCR\t0.1\t1.5\tdel(13q)\t0.89\t52,336\t1.00\t57\t\nP32\tYES\tIGHV3-48\t70\tFCR\tCR\t0.2\t5.1\tdel(11q)\t0.89\t53,793\t0.98\t4504\t\nP33\tYES\tIGVH3A-3B\t59\tFCR\tCR\t0\t2.1\tdel(6q)\t0.86\t59,041\t0.97\t6584\t\nP34\tYES\tIGHV1-3\t38\tFCR\tPR\t1\t3.0\tdel(13q)\t0.89\t60,526\t0.98\t2985\t\nTTFT time to first treatment (years) TTR time to relapse (years), ND not determined. Detected by karyotype and/or FISH (pre-treatment state)\n\n\n\nNext, we proceeded to methylation analysis at the individual case level. In addition to the DNA methylation changes observed after relapse, we also investigated the alterations which had occurred in comparison to normal B cells. We used as reference available data from two samples of peripheral blood memory B cells (MBC) from healthy donors recently reported by our group [12]. We found high correlation between the biological replicates (Pearson R = 0.99) of MBCs; thus, we merged and used them as a single reference sample.\n\nFirst, we compared the MBC versus the pre-treatment sample for each CLL case and noticed a variability in the Pearson R values ranging from 0.864 to 0.930: The number of DMCpGs (\|db\| ≥ 0.3), referred to as epigenetic burden (EB), ranged from 32,380 to 60,526 (Fig. 1a–c) (Table 1, Additional file 1: Table S1). All 34 CLL cases showed massive hypomethylation compared to MBC, in keeping with previous reports [13, 14] (Additional file 2: Figure S2).\nFig. 1 Intra-individual DNA methylation analysis reveals significant variability of epigenetic burden and relapse changes between CLL cases. a Dot plots showing the Pearson coefficient values (x-axis) representing the correlation of the MBC with the pre-treatment b values (left part, dark blue) and the correlation of the pre-treatment with the relapse b values (right part, light blue) of each CLL case (n = 34). b Density heatmaps displaying the frequencies of the b values for four selected CLL cases which showed the minimum and maximum Pearson R value after comparison of the b values of MBC (y-axis) and the pre-treatment state (x axis) which are depicted in (i) and (ii), and the b values of the relapse (y-axis) and pre-treatment state, which are depicted in (iii) and (iv). c Barplot, with each bar representing a different CLL case and showing the total number of DMCpGs related to the epigenetic burden (dark blue) plus the total number of DMCpGs related to relapse (light blue). d Barplots showing the percentage of hypermethylated (red color) and hypomethylated (green color) CpG sites at the relapse compared to the pre-treatment state, herein defined as relapse changes (RC), for all cases analyzed (upper part). The barplots in the lower part show the total number of the RCs for each case. Bars represent individual CLL cases\n\n\n\nNext, we compared the pre-treatment sample versus the relapse sample for each case and observed that the number of DMCpGs (\|db\| ≥ 0.3), referred to as relapse changes (RC), showed significant variability among patients ranging from 45 to 81,383 (Pearson R 0.822–0.996) (Fig. 1a–c) (Table 1, Additional file 1: Table S1). Twenty-three of the 34 (68%) samples after relapse showed a higher number of hypomethylated than hypermethylated CpGs compared to the pre-treatment state (Fig. 1d).\n\nInterestingly, we observed an overlap between the EB and RC, with the number of overlapping CpGs ranging from 13 to 22,853. Next, in order to examine the persistence of specific CpG sites affected at relapse, we calculated the number of overlapping CpGs/RC (Additional file 2: Figure S3). We found that most cases showed > 20% overlap between RC and EB at relapse, implying that DNA methylation changes, at least in part, occur in specific regions.\n\nDNA methylation changes in CLL cluster in specific genomic regions, chromatin states, and transcription factor binding sites\nWe characterized the DMCpGs detected in each CLL case regarding both the EB and the RC based on: (i) their genomic location, (ii) the respective chromatin state of MBC, and (iii) the transcription factor binding sites (TFBS) and performed enrichment analyses in order to gain insight into the biological function of the observed changes. Regarding genomic location and the chromatin state, we observed that the EB-hypomethylated CpGs were enriched in introns, gene bodies, and 3’ UTRs placed mainly in heterochromatin and strong and weak enhancers, while the EB hypermethylated CpGs were enriched in introns and TSS upstream regions (TSS1500) mostly located within polycomb repressed regions, poised and weak promoters, and strong enhancers in all 34 cases (Fig. 2a, c). The RC DMCpGs showed similarities as well as differences from the EB DMCpGs. More specifically, the RC-hypomethylated CpGs showed enrichment in introns, gene bodies, and 3’ UTRs as observed also in EB, but they were placed mainly in heterochromatin with only few cases placed in enhancers. Regarding the RC-hypermethylated CpGs, no consistent pattern was shared between cases. They preferentially clustered to the first exons, introns, and TSS upstream regions, which were located to poised promoters and polycomb-repressed regions, while enhancers were almost absent (Fig. 2b, d).\nFig. 2 Enrichment analysis of the epigenetic burden and relapse changes regarding genomic locations, chromatin states, and transcription factor binding sites. Genomic location enrichment analysis of a the epigenetic burden hypomethylated (green) and hypermethylated (red) CpGs for each CLL case and b the relapse hypomethylated (green) and hypermethylated (red) CpGs for each CLL case. Chromatin states enrichment analysis of c the epigenetic burden hypomethylated (green) and hypermethylated (red) CpGs for each CLL case and d the relapse hypomethylated and hypermethylated (red) CpGs for each CLL case. Each column represents a CLL case, with the cases sorted on x-axis based on the number of DMCpGs per case, from maximum to minimum. Each row represents a genomic element. The red color on heatmap displays the significant enrichment (p < 0.05) in each case for the respective genomic element (ActProm, active promoter; Hete LowSign, heterochromatin low signal; Het Repr, heterochromatin-repressed; PolRepr, polycomb repression; PoisProm, poised promoter; StrEnh1, strong enhancer 1; StrEnh2, strong enhancer 2; Txn_Elong, transcription elongation; Txn_Trans, transcription transition, Wk_Txn, weak transcription; WkEnh, weak enhancer; WkProm, weak promoter. e TFBS analysis of the hypo- and hypermethylated epigenetic burdens and relapse changes revealed significant enrichment for several TFs families (x-axis). The density of heatmap represents the number of patients which showed statistical significant enrichment per TFBS (FDR < 0.05)\n\n\n\nTFBS analysis revealed that both EB- and RC-hypomethylated CpGs were enriched (FDR < 0.05) for binding sites of a large series of TFs (Fig. 2e, Additional file 3: Table S2, and Additional file 4: Table S4). More specifically, in all cases, the EB-hypomethylated regions showed enrichment for several TFs relevant to B cell/CLL biology, including members of AP-1, GATA, IRF, POU, NFAT, STAT, and TCF families, as well as most members of HOX and FOX development-related TFs. This pattern was also observed on RC-hypomethylated regions, albeit in a lower number of analyzed cases (Fig. 2e, Additional file 3: Tables S2 and Additional file 4: Table S4). The EB- and RC-hypermethylated regions showed enrichment for TFBS in fewer CLL cases compared to the EB- and RC-hypomethylated regions, respectively (Fig. 2e, Additional file 5: Table S3, Additional file 6: Table S5 and Additional file 7: Table S6). Both hypo- and hypermethylated regions were enriched for TFBS of HOX and FOX families in contrast to TFBS such as FOS, JUN, IRF, and CEBP, which were specific for hypomethylated regions (Fig. 2e, Additional file 7: Table S6). Interestingly, the RC-hypermethylated regions were enriched for EGR2 and E2F4 binding sites in a large number of CLL cases (n = 14 and n = 18, respectively); however, most analyzed cases did not show similar enrichment for RC-hypomethylated or EB- (both hyper- and hypomethylated) regions (Additional file 7: Table S6).\n\nFinally, KEGG pathway enrichment analysis based on the DM genes, showed that, in almost all cases, EB-hypomethylated and hypermethylated-regions were enriched for pathways significant for CLL biology, e.g., ErbB, Phospholipase D, Ras, HIF, MAPK, Wnt, T, and B cell receptor, and Notch signaling pathways (Additional file 8: Table S7 and Additional file 9: Table S8). In contrast, a similar analysis for RC revealed enrichment in only a fraction of analyzed cases, especially those with a high number of changes, mainly on the hypermethylated gene sets (Chi-squared test, p < 0.05), e.g., pathways in cancer, calcium signaling pathway, and Rap1 signaling pathway (Additional file 9: Table S8).\n\nDNA methylation changes overtime associate with specific biological characteristics and clinical outcome\nBased on the results of the intra-individual methylation analysis, where each CLL case showed a different number of affected CpG sites compared to both the MBC and the relapse state, we explored potential correlations of the EB and RC with clinical and molecular characteristics.\n\nFirst, considering the fact that the DNA methylation profiles are affected by aging [15], we investigated the correlation between the age of patients with EB and RC, however, not finding any significant correlation (Spearman rho between RC and age = − 0.28, p = 0.11 \| Spearman rho between EB and age = 0.118 p = 0.50).\n\nNext, we noticed a significant inverse correlation between the EB and the time to first treatment (TTFT) (Spearman rho = − 0.42, p = 0.02) (Fig. 3a); no such correlation was identified with the time-to-relapse (TTR) (Spearman rho = − 0.112, p = 0.52). Moreover, we observed a significant positive correlation between the RC and the TTR (Spearman rho = 0.39, p = 0.02) (Fig. 3b). Relevant to mention, 13 of 34 cases could be characterized as early-relapsing since they relapsed within 2 years of treatment; notably, these cases displayed low or no evolution of DNA methylation. Put differently, we found very few RC in the early-relapsing cases compared to the rest which relapsed after 2 years of treatment, hereafter referred to as the late-relapsing group (median of DMCpGs 39 vs 4689, p = 0.002) (Fig. 3c), which, not unexpectedly, showed significantly longer TTR (median TTRs 1.3 vs 3.9 years, p = 4.32e-11).\nFig. 3 Associations of the epigenetic burden and the relapse changes with clinicobiological characteristics. a Scatter plot showing the epigenetic burden (EB) (y-axis) and the time to first treatment (TTFT) (x-axis) and their correlation coefficients (Spearman rho = 0.42, p = 0.02) for all 34 CLL cases b Scatter plots showing both the relapse changes (RC) (y-axis) and the time to relapse (TTR) (x-axis) and their correlation coefficients (rho = 0.39, p = 0.02) for all 34 CLL cases. The early-relapsing cases are displayed with green and the late-relapsing cases with blue. c Dot plot with median showing the RC of the early-relapsing and late-relapsing groups which show significant differences (p < 0.001). d Kaplan-Meier curves for time to relapse (TTR), with the early-relapsing cases relapse significant earlier than the late-relapsing (Log-test, p < 0.001). e Dot plot with median showing the EB of CLL cases with TP53 and non-TP53 aberrations which display significant differences (p < 0.05). f Columns represent patients (n = 34) and rows genes or cytogenetic abnormalities. The color scale represents the number of DMCpGs from blue (low) to red (high). Regarding cytogenetic abnormalities, black boxes state the presence of the aberration and white boxes the absence. Regarding gene mutations, gray boxes state the existence of whole-exome sequencing (WES) data available for the respective genes and the absence of mutation; gray boxes with asterisk () state the presence of mutation detected only at the pre-treatment state, black boxes the presence of mutation at relapse, and black boxes with asterisk represent the presence of mutation detected both at pre-treatment and at relapse state. White boxes state no availability of WES data. ND, not available data; p < 0.01, p < 0.05\n\n\n\nNext, we examined potential associations of epigenetic evolution regarding the EB and RC with particular biological characteristics of the malignant clones. Considering that the vast majority of cases (29/34, 85.2%) concerned U-CLL, we did not explore associations with immunogenetic features [i.e., the IGHV gene somatic hypermutation status] and, instead, decided to focus on genomic aberrations. To this end, we used available cytogenetic data (FISH and/or karyotype) regarding the Dohner model abnormalities [i.e., del(11q), del(13q), del(17q), and trisomy 12] for all 34 cases. Moreover, we used existing whole-exome sequencing (WES) data for 26/34 cases reported in a recent publication from our group [16] and examined potential associations with mutations within the ATM, BIRC3, EGR2, MGA, NFKBIE, NOTCH1, SF3B1, and TP53 genes. Additionally, for 16/26 cases, we had available data for clonal evolution (all mutations were documented at both pretreatment and relapse and assigned to separate clusters using the SciClone25 clustering tool). Interestingly, cases carrying TP53 aberrations showed significantly higher EB versus TP53-wildtype CLL cases (median-EB = 45,848.5 vs 42,384, respectively, p = 0.0176) (Fig. 3d). Additionally, most cases with available data (14/16), previously published [16], showed relapse-specific subclones/clusters which expanded significantly to become the dominant clone at relapse; the remaining 2 cases showing a more stable intraclonal composition over time accompanied by no epigenetic evolution after relapse (RC = 117 and 1263). Relevant to mention, the cases analyzed in our study were treated with FCR at a time when signaling inhibitors, currently considered as the standard of care for TP53 aberrant cases, were not available; hence, a proportion of cases who received FCR treatment carried such aberrations. All the examined prognostic markers are summarized graphically in Fig. 3e while the analysis regarding their association with the EB and RC is depicted in Additional file 2: Figures S4-S5.\n\nDiscussion\nRecent studies have demonstrated extensive genetic heterogeneity underlying clonal evolution in CLL patients with adverse clinical outcomes [16, 17]. Besides genetic events, however, CLL is also characterized by epigenetic alterations, with DNA methylation profiles being the best studied thus far [2, 14, 18–20]. Interestingly, a recent study demonstrated that CLL cases belonging to the memory B-cell-like epigenetic subgroup [21] showed a favorable response to FCR [22]. However, insight into how the epigenetic mechanisms might be implicated in disease evolution, particularly the response to treatment, is still lagging.\n\nIn order to obtain evidence regarding this issue, we analyzed longitudinal samples from a series of 34 CLL patients mostly (n = 31) treated with the FCR regimen in order to explore DNA methylation changes overtime and whether these may be associated with the patterns of clinical response. At cohort level, we did not observe recurrent DNA methylation changes, in line with two previous studies [2, 4]. This could be attributed, at least in part, to the large heterogeneity characterizing the DNA methylation profile of CLL cases [23, 24], even those carrying IGHV genes with concordant somatic hypermutation status [12] as in the present series, where the vast majority of cases concerned U-CLL.\n\nConsidering the above, we focused on each individual patient separately and examined both the epigenetic burder (EB), i.e., the methylation changes that tumor cells acquire compared to memory B cells form healthy donors (considering that all CLL cases globally resemble memory B cells) [3] but also the changes between the pre-treatment sample versus the relapse sample, referred to as relapse changes (RC). This intra-individual analysis confirmed once again the pronounced biological heterogeneity of CLL, since great variability was noted between cases regarding both the EB but also the RC. In all cases, CLL cells were characterized by extensive epigenetic reprogramming displaying massive hypomethylation compared to memory B cells, in keeping with previous studies [3, 14, 25]. Relevant to mention, it was recently shown that the number of epigenetic changes that a tumor acquires compared to its cellular origin, i.e., the EB, may be a powerful predictor of clinical aggressiveness in mantle cell lymphoma (MCL) [26] where patients with high EB experienced a worse clinical outcome. Following the same approach, we here report a similar observation also for CLL, since we found that the higher the EB the shorter the TTFT.\n\nRegarding the RCs, we found very high inter-patient variability; some cases had stable epigenetic profiles while others showed significant epigenetic evolution after relapse, with a mixed pattern of hypomethylated or hypermethylated events at relapse. Notably, the number of RCs was positively correlated with the time to relapse. Especially, those cases relapsing within 2 years of treatment (“early-relapsing”) displayed low or no evolution of DNA methylation. Our observation appears to contradict a recent publication [4], which reported that epigenetic evolution after treatment is linked with short time to post-therapy events (treatment and death). These discrepant results might be attributed to differences in the composition and size of the respective study cohorts (21 vs 34 cases in our series) as well as the administered treatments (purine analogs and/or alkylating agents vs FCR in our series), but also differences in the applied data analysis strategies.\n\nIn an attempt to identify a unifying line of events, we sought for connections regarding the methylation changes occurring overtime and also explored associations with genomic alterations and other clinicobiological features. Our results suggest that most CLL cases carrying TP53 aberrations display higher EB compared to the rest and confirm the association of higher EB with shorter TTFT. This finding links adverse-prognostic genomic aberrations with a higher propensity to evolve epigenetically, perhaps as a consequence of high rates of proliferation [27–29]. Such epigenetic evolution might potentially facilitate subclonal expansion as also suggested by a previous study which showed that a high level of alterations in DNA methylation was accompanied with a greater probability to develop new subclones [23]. Admittedly, one could also argue for the opposite, namely that the genomic evolution should fuel the epigenomic evolution, especially considering the well-known complex interplay between genetics and epigenetics whereby the genomic instability could influence the epigenetic evolution and vice versa [30, 31]. Relevant to mention in this respect, p53 gain of function mutants have been found to bind to and upregulate chromatin regulatory genes that may influence the DNA methylation patterns [32]. Turning to RC, we observed significant correlation with TTR but also great heterogeneity. Most early-relapsing cases showed low or no evolution of the respective DNA methylation profiles suggesting that these cases did not have sufficient time to accumulate DNA methylation changes and/or were more progressive. In such cases, treatment with FCR does not appear to impact significantly on the clonal behavior, leading to the re-emergence of a clone that is not fundamentally different from the pre-treatment clone, at least at the level of resolution of our study.\n\nFrom a qualitative point of view, the majority of methylation changes at relapse appear to follow a pattern where hypomethylation events cluster mainly in gene bodies and heterochromatic regions while hypermethylation events cluster in promoters and polycomb-related regions. This pattern is also observed during B cell differentiation (e.g., long-lived memory/plasma cells) as well as in other tumors and may represent a passive result of, e.g., proliferation history and cellular longevity [14, 25, 33]. Relevant to mention, in a previous study from our group, we found that the histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), is upregulated during the disease course in CLL, especially at relapse [34]. In another recent study, Smith and colleagues [5] identified modest recurrent DNA methylation changes during CLL progression in CpG sites enriched for regions near targets of the PRC2 complex.\n\nSubstantial evidence supports an interplay between transcription factors and DNA methylation both during normal B cell development but also during the course of CLL [3, 14, 25]. In the present study, we observed that genomic regions which became hypomethylated prior to treatment initiation but also after relapse were enriched for binding sites of several transcription factor families relevant to B cell/CLL biology, including the GATA, STAT, HOX, and FOX transcription factors (TFs). Among others, we also observed AP-1, POU, and IRF which were descripted to target hypomethylated regions during normal B cell maturation [3] and also the NFAT family which has been associated with hypomethylated regions in CLL [3, 35]. Interestingly, de novo active chromatin regions in CLL compared to normal B cells were very recently reported to be enriched in FOX TF family binding sites as well as the NFAT and TCF/LEF TFs [36]. On the other hand, EGR2 and E2F4 were found to be specifically associated with regions hypermethylated at relapse, implying a direct connection with the relapse mechanism. Of note, EGR2 mutations have been detected in clinically aggressive CLL subgroups [37] while E2F4, a key regulator of the cell cycle, has been reported deregulated in both Burkitt lymphoma and diffuse large B cell lymphoma [38].\n\nConclusions\nIn conclusion, this study highlights that DNA methylation profiles are modulated during CLL evolution, particularly in response to chemoimmunotherapy with the FCR regimen. These distinct dynamics of DNA methylation were linked to clinicobiological characteristics, including genomic aberrations, time-to-first-treatment, and response to treatment as assessed by time-to-relapse. These alterations mainly occurred in specific genomic regions, following a pattern similar to that observed in long-lived memory/plasma cells and other tumor types, while they were associated with binding sites of transcription factors implicated in B cell and CLL biology.\n\nMethods\nPatient samples\nEighty peripheral blood (PB) samples from 40 CLL patients from 7 collaborating institutions in the Czech Republic, Germany, Greece, Italy, Sweden, and the UK were included in the study. All cases were diagnosed with CLL according to the guidelines of the International Workshop Chronic Lymphocytic Leukemia/National Cancer Institute (iwCLL/NCI) [39]. The first sample for each patient was collected before the first treatment and is characterized as the pre-treatment sample while the second soon after clinically documented relapse and is characterized as the post-treatment (i.e., after relapse) sample. Thirty-six of the 40 patients were treated with FCR, 2/40 with FC, and one each of the remaining 2 cases with BR or FCMR. The study was approved by the local Ethics Review Committee of the participating institutions. Demographic, clinical, and biological data for the patient cohort is listed in Additional file 1: Table S1.\n\nCell separation\nThe tumor load of CLL PB samples ranged from 51 to 100%. Purified CLL cell samples (n = 46) were prepared with negative selection of CD19+ B cells from whole blood using the RosetteSep B-cell enrichment kit (StemCell Technologies, Vancouver, BC, Canada) following the manufacturer’s instructions.\n\nDNA methylation array analysis\nPreparation of DNA samples and processing the DNA methylation signal of the Infinium HumanMethylation 450K BeadChip were performed in R using the “minfi” package. We used the subset-quantile within array normalization (SWAN) [40] that corrects for the technical differences between the Infinium I and II assay designs and produces a smoother overall beta value distribution. Moreover, we developed and optimized an analysis pipeline with several filters (i.e., discarding CpGs with low detection p values, sex-specific CpGs, CpGs showing individual-specific methylation, and CpGs overlapping with SNPs). Regarding batch effects, we analyzed 10 patient samples in two different batches in order to check the Pearson R for each sample between the two batches (Pearson R ranging from 0.9932 to 0.9970). Moreover, the in silico purification was performed based on a new approach we previously developed for deconvolution of the DNA methylation signal of mixed subpopulations helping to isolate in silico the DNA methylation levels of the tumor cells [26, 41] (Additional file 2: Figure S6). It is widely acknowledged that CLL cells resemble antigen-experienced B cells, particularly displaying a phenotype more similar to that of memory B cells [42]. Therefore, using memory B cells as a normal counterpart to detect epigenetic changes in CLL patients appears to represent a rational, in fact perhaps the most appropriate, healthy control. With this in mind, we used as reference for normal B cells two samples of peripheral blood memory B cells (MBC) from healthy donors recently reported by our group [12].\n\nData availability\nThe dataset supporting the conclusions of this article is available in the ΕΒΙ repository, https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7575, reference number E-MTAB-7575.\n\nGenomic and functional annotation of CpGs\nThe differentially methylated CpG sites (DMCpGs) were characterized based on their genomic locations (e.g., TSS, exon, and intron) and the chromatin states (ChIP-seq for 6 histone marks) from a pool of memory B cells obtained from healthy male donors with age ranging from 56 to 62 years recently published [26] (the above reference for the functional annotation is age-matched with the present study group with a mean age 56.5 years). Moreover, we investigated the overlap between the DMCpGs and the JASPAR database of transcription factor binding sites [43] (Additional file 2: Supplementary Methods). Finally, we performed KEGG-pathway enrichment analysis using the differentially methylated genes.\n\nStatistical analysis and visualization\nDifferential methylation analysis (DMA) was performed for the CpG sites of methylation profiles between two conditions. CpG sites were considered as differentially methylated when the following criteria were met, specifically, a minimum absolute difference of 0.3 between mean beta-values (beta difference, db) of the two subgroups and a p value criterion when appropriate. We used the Wilcoxon-paired test for paired samples applying FDR for the correction. The Kruskal test was used in a different context for testing differences between independent samples. Data analysis was carried out in the R environment (3.5.1 version). More details can be found in the Additional file 2: Supplementary Methods.\n\nSupplementary information\n\nAdditional file 1: Table S1. Clinicobiological data and results of the intra-individual DNA methylation analysis for the patient cohort.\n\n \nAdditional file 2: Supplementary Methods. Figure S1. A. Hierarchical clustering of all 68 samples, based on the methylation levels of 451756 CpG sites analyzed per case. 30/34 cases showed strong intra-individual similarity. B. Principal component analysis showing components 1 and 2 in the pre treatment and post relapse stage based on 451756 CpG sites. Figure S2. Barplots showing the percentage of hypermethylated (red color) and hypomethylated (green color) CpG sites revealed after the comparison of the MBC (memory B cells) with the pre-treatment state of each case analyzed. Figure S3. Dot plots with median showing the RC in subgroups of CLL cases based on the genomic aberrations. Figure S4. Dot plots with median showing the EB in subgroups of CLL cases based on the genomic aberrations. Figure S5. Dot plots with median showing the RC in subgroups of CLL cases based on the genomic aberrations. Figure S6. Graphical description of the study aim, the study group and the methods used. We performed deconvolution of DNA methylation data, since a part of CLL samples was characterized bythe tumor load <95%. Estimation of the proportion of hematopoietic cell subpopulations in CLL samples and sorted B cells, CD8+ T cells, CD4+ T cells, natural killer cells, monocytes and granulocytes. Sorted cell subpopulations (a right part of the heatmap) are correctly predicted and CLL cases show a gradient from lower to higher proportion of B cells (a left part of the heatmap).\n\n \nAdditional file 3: Table S2. TFBS enrichment analysis of the hypomethylated epigenetic burdens revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 4: Table S4. TFBS enrichment analysis of the hypomethylated relapse changes revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 5: Table S3. TFBS enrichment analysis of the hypermethylated epigenetic burden revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 6: Table S5. TFBS enrichment analysis of the hypermethylated relapse changes revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 7: Table S6. TFBS enrichment analysis of the hypo- and hypermethylated epigenetic burdens and relapse changes separately, revealed common TFs among CLL cases.\n\n \nAdditional file 8: Table S7. KEGG enrichment analysis of the epigenetic burden hypo- and hyper- methylated genes separately, revealed common pathways among CLL cases.\n\n \nAdditional file 9: Table S8. KEGG enrichment analysis of the relapse hypo- and hyper- methylated genes separately, revealed common pathways among CLL cases.\n\n \n\n\nAbbreviations\nBRBendamustine-rituximab\n\nCLLChronic lymphocytic leukemia\n\nDMADifferential methylation analysis\n\nDMCpGsDifferentially methylated CpG sites\n\nEBEgenetic burden\n\nFCFludarabine-cyclophosphamide\n\nFCMRFludarabine-cyclophosphamide-rituximab+mitoxantrone\n\nFCRFludarabine-cyclophosphamide-rituximab\n\niwCLL/NCIInternational Workshop Chronic Lymphocytic Leukemia/National Cancer Institute\n\nMBCMemory B cells\n\nM-CLLChronic lymphocytic leukemia cases carrying mutated immunoglobulin receptors\n\nPBPeripheral blood\n\nRCRelapse changes\n\nTFBSTranscription factor binding sites\n\nTTFTTime-to-first-treatment\n\nTTRTime-to-relapse\n\nU-CLLChronic lymphocytic leukemia cases carrying unmutated immunoglobulin receptors\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nMaria Tsagiopoulou and Nikos Papakonstantinou contributed equally to this work.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s13148-019-0783-1.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nMT performed the study and wrote the manuscript; NP designed the research, performed the study and wrote the manuscript; TM performed data and statistical analysis and assisted in data interpretation; LM, VL, MD-F, AM, NC, ACQ., KP, SB, PK, DP, SL, MG and AH assisted in research, data analysis, and interpretation; DO, AA, LT, MR, SP, NS and PG, provided patient samples; JIMS assisted in data interpretation and revised the manuscript; CP designed research, provided materials and patient samples; RR provided materials, patient samples and revised the manuscript; KS designed and supervised the research and wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported in part by the Horizon 2020 project AEGLE funded by the European Union; the KRIPIS action, funded by the General Secretariat for Research and Technology of Greece; the Ministry of Health of the Czech Republic for conceptual development of research organization FNBr 65269705 and the project CEITEC2020 LQ1601 from the Ministry of Education, Youth and Sports of the Czech Republic; by Associazione Italiana per la Ricerca sul Cancro AIRC (5 per mille Research Program on Metastasis # 21198), Milano, Italy; ERA-NET TRANSCAN-2 JTC 2014, GCH-CLL #143; MIUR-PRIN 2015ZMRFEA, Roma, Italy; the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, Radiumhemmets Forskningsfonder, Stockholm, Lion’s Cancer Research Foundation, Uppsala, Marcus Borgström’s Foundation, Uppsala, and Selander’s Foundation, Uppsala.\n\nMT is a recipient of a fellowship from the State Scholarships Foundation of Greece; and a short-term collaboration award by the European Haematology Association.\n\nAvailability of data and materials\nThe dataset(s) supporting the conclusions of this article is(are) available in the ΕΒΙ repository, https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7575, reference number E-MTAB-7575.\n\nEthics approval and consent to participate\nThe study was approved by the local Ethics Review Committee for the Institute of Applied Biosciences/Centre for Research and Technology Hellas (Ref. No: ETH.COM-45).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nPG has received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. Has received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Novartis, and Sunesis. RR has received honoraria from AbbVie, Janssen, Illumina, and Roche. KS received research support from Janssen Pharmaceuticals and Roche SA. All other authors declare no competing interests.\n==== Refs\nReferences\n1. Mansouri L Wierzbinska JA Plass C Rosenquist R Epigenetic deregulation in chronic lymphocytic leukemia: clinical and biological impact Semin Cancer Biol 2018 51 1 11 10.1016/j.semcancer.2018.02.001 29427646 \n2. 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Khan A Fornes O Stigliani A Gheorghe M Castro-Mondragon JA van der Lee R JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework Nucleic Acids Res 2018 46 D1 D260 D2D6 10.1093/nar/gkx1126 29140473\n\n", "fulltext_license": "CC BY", "issn_linking": "1868-7075", "issue": "11(1)", "journal": "Clinical epigenetics", "keywords": "CLL; Chemoimmunotherapy; DNA methylation; Microarray analysis; Relapse", "medline_ta": "Clin Epigenetics", "mesh_terms": "D000328:Adult; D000368:Aged; D003520:Cyclophosphamide; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine", "nlm_unique_id": "101516977", "other_id": null, "pages": "177", "pmc": null, "pmid": "31791414", "pubdate": "2019-12-02", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "22475873;26053498;27191993;22394601;19897574;29140473;21927626;26065654;24138928;26331536;20888994;11733577;26486789;26492934;24465226;22534504;21239840;28921505;29099488;28540331;23064414;24356097;28851627;29540348;27846393;29427646;25151957;30447004;22922567;25860294;26276669;26780610;1382719;23154584;26691213;27890934;31434681;23908595;26675346;25490447;29785028;22703947;23415222", "title": "DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy.", "title_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy" }	[ { "companynumb": "GR-ROCHE-2516742", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL.. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY... CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17276114, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516883", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17263058, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515915", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "M T, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11(177):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200117", "receivedate": "20200117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17281078, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515899", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200519", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17260988, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "GR-ROCHE-2516774", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17262836, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516395", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS. 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265236, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515870", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. 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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. 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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. 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CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17260989, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2519002", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L,LJUNGSTROM V, DURAN-FERRER M ET AL DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS. 2019?11(1):177-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516953", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268102, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515153", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M, ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11(1):177-88.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17271162, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515896", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "M T, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L ,LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(1):177-177.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17261322, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516902", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17263000, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516765", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):177-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17274980, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516411", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(177):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265290, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2517979", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "M T, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17275355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516747", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17274955, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515154", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M, ET AL.. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(1):177-188.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17262831, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515916", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200521", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17271161, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "GR-ROCHE-2515858", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. 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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):177-188.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-MYLANLABS-2020M1019344", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL... DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. .. CLINICAL EPIGENETICS. 2019?11(1):1-12", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200225", "receivedate": "20200225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17457463, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2612734", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(177):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200603", "receivedate": "20200603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17853183, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]
{ "abstract": "In this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.", "affiliations": "Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel, Switzerland.;Regional Pharmacovigilance Centre Basel, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Swissmedic, Schweizerisches Heilmittelinstitut, Bern, Switzerland.;Division of Internal Medicine, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.", "authors": "Istampoulouoglou\|Ioanna\|I\|;Zimmermanns\|Barbara\|B\|;Grandinetti\|Tanja\|T\|;Marzolini\|Catia\|C\|;Harings-Kaim\|Annette\|A\|;Koechlin-Lemke\|Sarah\|S\|;Scholz\|Irene\|I\|;Bassetti\|Stefano\|S\|;Leuppi-Taegtmeyer\|Anne B\|AB\|", "chemical_list": null, "country": "Qatar", "delete": false, "doi": "10.21542/gcsp.2021.11", "fulltext": "\n==== Front\nGlob Cardiol Sci Pract\nGlob Cardiol Sci Pract\nGCSP\nGCSP\nGlobal Cardiology Science & Practice\n2305-7823\nMagdi Yacoub Heart Foundation UK\n\ngcsp.2021.11\n10.21542/gcsp.2021.11\nPharmacovigilance\nCardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre\nIstampoulouoglou Ioanna 16§\nZimmermanns Barbara 126§\nGrandinetti Tanja 16\nMarzolini Catia 36\nHarings-Kaim Annette 26\nKoechlin-Lemke Sarah 126\nScholz Irene 4\nBassetti Stefano 56\nLeuppi-Taegtmeyer Anne B 126anne.leuppi-taegtmeyer@usb.ch\n\n1 Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland\n2 Regional Pharmacovigilance Centre Basel, University Hospital Basel, Switzerland\n3 Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel, Switzerland\n4 Swissmedic, Schweizerisches Heilmittelinstitut, Bern, Switzerland\n5 Division of Internal Medicine, University Hospital Basel, Switzerland\n6 University of Basel, Basel, Switzerland\n§ shared first authorship.\n\n30 6 2021\n30 6 2021\n2021 2 e20211111 4 2021\n31 5 2021\nCopyright ©2021 The Author(s)\n2021\nThe Author(s), licensee Magdi Yacoub Institute.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.\nIn this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.\n==== Body\nIntroduction\n\nThe antiretroviral drugs lopinavir/ritonavir (LPV/r) and the antimalaria drug hydroxychloroquine (HCQ) were initially proposed as potential treatments of COVID-19. Based on currently available data, the benefit-risk profile of these drugs cannot be considered favourable because they did not demonstrate efficacy and there are concerns about their safety1. Prolongation of the QTc interval and the associated increased risk of sudden cardiac death are the most serious adverse reactions2,3.\n\nWith the exception of a few recommendations4, no official guidelines currently exist for handling the risk of drug-induced QTc time prolongation in clinical practice, or for monitoring the QTc interval during therapy with QTc-prolonging drugs. Therefore, management is not uniform and differs among institutions and practitioners. In addition to a baseline ECG, some doctors perform an additional ECG check after the first dose when the maximum plasma concentration of the relevant drug has been reached, while others carry out a further ECG check only after the steady state of the relevant drug has been reached.\n\nAdditionally, it is known, that COVID-19 itself can affect the cardiovascular system and that viral infections predispose patients to cardiac arrhythmia due to metabolic dysfunction, myocardial inflammation and activation of the sympathetic nervous system. Consequently, the development of cardiac arrhythmia in COVID-19 patients is increased2,3,6.\n\nIn this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with LPV/r and HCQ. The cases were reported to our regional pharmacovigilance centre in April 2020. There, pharmacovigilance assessments according to the World Health Organisation (WHO) criteria were performed8.\n\nA spontaneous pharmacovigilance report is a snapshot that provides information on whether a drug or vaccine could in principle be associated with a suspected adverse effect. It also assesses the degree of association between the drug and the suspected adverse drug reaction (ADR), namely as certain, likely, possible, unlikely or unclassifiable. It must be noted that a spontaneous report cannot answer the question whether the symptoms observed in a particular patient are wholly attributable to the drug intake. This question can only be answered by an individual medical opinion. Nevertheless, in Switzerland, medical professionals and all those who manufacture, administer or dispense therapeutic medicinal products – including medical personnel who are authorised to do so – are obliged by law to report the occurrence of ADRs to the national regulatory authority for medicinal products, Swissmedic.\n\nCase presentations\n\nThe relevant demographic, clinical, and laboratory information for each patient case and details about each adverse drug reaction (ADR) as well as the outcome and ultimate pharmacovigilance assessment are given in Table 1.\n\n10.7717/gcsp.202111/table-1 Table 1 Demographic, clinical, and laboratory characteristics of the clinical cases and ADR details.\n\nPatient number\tAge/Sex\tCOVID-19 diagnosis\tComorbidities\tSuspected drugs\tADR\tLatency to ADR\tIntervention\tQTc-maximum values (latency time)\tWHO causality assessment8\tADR outcome at time of PV report\t\n1.\t80-year-old male\tBilateral pneumonia & severe ARDS\t1–2, 6\tLPV/r, HCQ LPV-trough level 26.9 mg/l (day 3 of combination therapy)\tQTc time prolongation from baseline value of 417 msec\tDay 3 of combination therapy\tLPV/r and HCQ stopped after 3 days of combination therapy\t500 msec (5 days after triple combination therapy-stop)\tPossible for all drugs, alone or in combination\tRecovered without sequelae\t\n2.\t82-year-old male\tEnteritis, bilateral pneumonia & severe ARDS\t1–5\tErythromycin, LPV/r, HCQ LPV-trough level 30.1 mg/l (day 3 of LPV/r therapy)\tQTc time prolongation from baseline value of 416 msec\tDay 2 of erythromycin Day 9 of LPV/r 9 days after end of HCQ\tErythromycin and LPV/r stopped after 2 & 9 days of therapy, respectively\t570 msec (1 day after stopping erythromycin- & LPV/r and 10 days after stopping HCQ)\tPossible for all drugs, alone or in combination\tRecovered without sequelae\t\n3.\t77-year-old male\tPneumonia\t1, 5, 7–11\tLPV/r, HCQ LPV-trough level 27.0 mg/l (day 2 of LPV/r therapy) & 20.6 mg/l (day 5 of LPV/r therapy)\tQTc time prolongation from baseline value of 419 msec\tDay 1 of combination therapy\tLPV/r and HCQ stopped after 6 & 3 days of therapy, respectively\t535 msec (day 1 of triple combination therapy)\tPossible for all drugs, alone or in combination\tRecovering\t\nNotes.\n\nADR: adverse drug reaction, HCQ: hydroxychloroquine (800 mg on day 1–2 and 400 mg on day 3), LPV/r: lopinavir/ritonavir (on day 1: 2 × 800/200 mg, then 2 × 400/100 mg/day for 2, 7 or 5 days in cases 1, 2 & 3 respectively), PV: pharmacovigilance, WHO: World Health Organization.\n\nComorbidities: 1. Arterial hypertension, 2. Type 2 diabetes mellitus, 3. Hypertriglyceridemia, 4. Obesity 5. Previous stroke, 6. Previous nephrectomy (normal creatinine value), 7. Chronic renal impairment, 8. Liver cirrhosis, 9. Cardiomyopathy with pacemaker implantation, 10. Recurrent acute polyarticular gout attacks, 11. Lumbovertebral pain syndrome.\n\nAll three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received an off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.\n\nThe first case relates to an 80-year-old male patient hospitalized with bilateral pneumonia and severe ARDS due to a COVID-19 infection, for whom a combination therapy with LPV/r and HCQ was initiated nine days after the initial symptoms developed. Two days later, significant QTc time prolongation was observed and so LPV/r and HCQ were stopped. An intervention for the ECG changes was not necessary. Patients were continuously assessed for arrhythmias, which did not occur in any cases. The QTc time was monitored using 12-lead ECGs and returned to normal within two weeks. The patient recovered from COVID-19 and could be transferred to rehabilitation. His treatment also included tocilizumab and amoxicillin/clavulanic acid, which were not judged to be associated with the QTc time prolongation.\n\nThe second case was an 82-year-old male patient hospitalized with enteritis, bilateral pneumonia and severe ARDS due to COVID-19 infection. He developed QTc time prolongation, which was attributed by his treating doctor as drug induced. Suspected drugs were LPV/r, HCQ and erythromycin. Other causes or risk factors for QTc time prolongation such as underlying cardiac disease or hypokalemia in the context of COVID-19 associated enteritis were not reported. Therapy with LPV/r was terminated 1 day earlier than planned; and so was the therapy with erythromycin. The therapy with HCQ had already ended before the development of the ADR. As far as can be determined, no cardiac arrhythmias occurred and the QTc time returned to baseline.\n\nThe third case refers to a 77-year-old male patient hospitalized with underlying cardiomyopathy (VDD-pacemaker – i.e., ventricle paced, atrium and ventricle sensed – in situ), initially admitted with suspected atypical pneumonia. During the course of the admission the patient was diagnosed with COVID-19 pneumonia and non-invasive ventilation was necessary. The patient was sufficiently oxygenated with 4–6 liters oxygen/min via an oxygen mask. A prolonged QTc time was observed on the same day that therapy with LPV/r and HCQ was initiated. HCQ was continued for two more days and LPV/r for five more days. There were no reports of arrhythmia and the patient made a complete recovery, despite requiring a period of haemodialysis for acute renal failure of multifactorial origin.\n\nPharmacovigilance discussion\n\nLPV/r, HCQ, and erythromycin can all prolong the QTc interval. HCQ and erythromycin are known to cause relevant QTc time prolongation, which according to the latest AHA Recommendations for the Standardization and Interpretation of the Electrocardiogram, is a QTc time ≥ 460 msec in females and ≥ 450 msec in males7; QTc times > 500 msec are generally considered to carry a high risk for torsades de pointes (TdP) arrhythmia15. Although TdP usually ends spontaneously, it can rarely turn into ventricular fibrillation and cardiac arrest with a potentially lethal outcome.\n\nThe mechanism of QTc time prolongation by LPV/r, HCQ and erythromycin is through inhibition of the cardiac hERG (human ether-a-go-go related gene) potassium channels13. Inhibition of hERG channels is largely dose-/concentration-dependent and can be additively increased if hERG blockers are given together13. If QTc time increases by more than 60 msec or over 500 msec, the causative drugs should be discontinued right away14.\n\nThe following cardiac ADRs are described in the drug product information for LPV/r10: as occurring occasionally: atherosclerosis resulting in myocardial infarction, atrioventricular conduction disorder or tricuspid regurgitation. According to post-marketing experience, cases of bradyarrhythmia are also known, but cases of relevant QTc time prolongation, TdP or ventricular fibrillation have not been reported. Based on a controlled, randomized cross-over study in healthy volunteers10 receiving therapeutic doses (400/100 mg LPV/r 2x/day) or supratherapeutic doses (800/200 mg 2x/day), the maximum mean difference (upper limit 95% confidence interval) of the QTc interval with 400/100 mg LPV/r twice daily compared to placebo was 3.6 (6.3) msec; and 13.1 (15.8) msec for supratherapeutic doses of 800/200 mg LPV/r twice daily compared to placebo. QTc time prolongation of ≥ 60 msec from baseline or a QTc in excess of 500 msec did not occur. The product information for LPV/r also points out an increased risk of cardiac complications when combined with drugs known to induce a prolongation of the QTc interval, such as erythromycin or HCQ. According to Eudravigilance data, a QTc time prolongation was described in 17 spontaneous case reports during LPV/r therapy for COVID-193. The global WHO database for reporting ADRs has so far received 25 reports of QTc time prolongation and 7 cases of TdP ventricular arrhythmia following LPV/r therapy out of a total 12,313 reports since 200116. Overall 1,996 ADRs were reported in association with LPV/r in 2020 compared to 424 in 2019 (approximately a 5-fold increase), consistent with widespread use of this drug during the COVID-19 pandemic16.\n\nECG changes are labelled as occasional ADRs in the product information for HCQ11. There are warnings that HCQ may increase the QTc interval in patients with specific clinical risk factors (e.g., heart disease, cardiac arrhythmias, hypokalemia, hypomagnesemia) and when there is simultaneous treatment with substances which also prolong the QTc interval. Dose-dependency with regard to the extent to which the QTc interval is prolonged has been described. The dose in this case was the same as that which is used to treat malaria (1 × 800 mg, then 400 mg/day for 2–3 days). The global WHO database for reporting ADRs has so far received 47 reports of QTc time prolongation and 78 reports of torsades de pointes ventricular arrhythmia in association with HCQ therapy, out of a total of 29,487 reports since 196816. Overall ADR-reporting increased 1.6-fold between 2019 and 2020, consistent with widespread use of this drug during the COVID-19 pandemic16.\n\nIn the Swiss product information for erythromycin, a QTc time prolongation is listed as a rare ADR and simultaneous use of drugs that can also lead to a prolongation of the QTc interval is listed as a contraindication12.\n\nLPV is highly metabolized by the hepatic cytochrome P450 (CYP450) system, primarily by the isoenzyme CYP3A and ritonavir to a lesser extent additionally by CYP2D6. Ritonavir, a potent inhibitor of CYP3A, inhibits the metabolism of LPV, leading to an increase in plasma levels of LPV (so-called “pharmaco-enhancement”). The effective half-life of LPV in this combination is 5–6 hours (steady state is reached after 25–30 hours). The half-life of ritonavir is 3–5 hours (steady state reached after 15–25 hours) so that in theory, concentration-dependent ADRs related to LPV/r can be observed as early as during the first two days of therapy and cease within a few hours to a few days after drug discontinuation. The target LPV trough level at steady state (before the 5th administration) was > 10 mg/l for the treatment of SARS-CoV-2 with LPV/r at the centre which reported the cases. All patients reported here had LPV trough levels exceeding this target, in keeping with the observation by Marzolini and colleagues, that LPV trough levels are approximately 3.5 times higher in patients with COVID-19 compared to patients with HIV infection5.\n\nLPV/r are predominantly metabolized and eliminated via the liver, so that increased plasma concentrations and increased liver toxicity are to be expected in patients with liver dysfunction. As COVID-19 can cause liver dysfunction, this might be one explanation for the reduced LPV clearance observed in these patients9. A more likely explanation for the reduced LPV clearance is COVID-19-associated inflammation, which inhibits drug metabolism, particularly through inhibiting the activity of CYP3A45. Since excretion of LPV via the kidney is negligible, no reduced overall clearance is to be expected in patients with renal insufficiency. At present, there are no data for ritonavir for this specific group of patients.\n\nHCQ is predominantly renally eliminated (69%) and partially metabolized by CYP2C8 and CYP3A4 (see Figure 1)17,18. The elimination kinetics follow a two-compartment model. For this reason, ADRs related to HCQ can in theory occur not only during therapy but also a few days to two months after stopping the drug.\n\n10.7717/gcsp.202111/fig-1 Figure 1. Major pathways of hydroxychloroquine metabolism.\n\nErythromycin is metabolized by the hepatic CYP450 system, primarily by the isoenzyme CYP3A4 and to a lesser extent by CYP2B6. Moreover, erythromycin is a moderate inhibitor of CYP3A4. It is mainly eliminated via the liver and gallbladder and due to its short plasma half-life of 1–2 hours, ADRs related to erythromycin can happen on the first day of therapy.\n\nThe combination of LPV/r, HCQ and erythromycin is problematic both due to pharmacokinetic and pharmacodynamic drug-drug interactions. Combining HCQ and erythromycin – two known QTc-prolonging drugs – with LPV/r, a drug with potential QTc time prolongation, can result in an additively increased risk of QTc time prolongation and TdP.\n\nRitonavir and erythromycin, which are substrates and inhibitors of CYP3A4 at the same time, inhibit both their metabolism and that of lopinavir, another CYP3A4 substrate, leading to a significant higher plasma level of LPV and erythromycin; and subsequently increased risk of ADR, particularly additive QTc time prolongation. The fact that COVID-19-associated inflammation itself predisposes to cardiac arrhythmia and inhibits the activity of CYP3A4, potentiates the risk of drug induced-QTc prolongation even more as evidenced by the increased reporting of QTc prolongation during the COVID-19 pandemic, particularly among male patients19.\n\nClinical implications for prescribing and monitoring\n\nBefore prescribing QTc-prolonging drugs, not only should the potential risk of QTc time prolongation associated with the proposed drug and of all current co-medication be taken into account, but also patient-related and in part modifiable risk factors.\n\nThese risk factors include the female sex, age > 65 years, structural heart diseases, such as heart failure with low ventricular ejection fraction, left ventricular hypertrophy, and myocardial infarction, an impaired hepatic or renal function, an uncorrected electrolyte disturbance like hypokalemia, hypomagnesemia or hypocalcemia and an untreated hypothyroidism4.\n\nPotassium, magnesium and calcium values, as well as the thyroid function, were not reported in our three patients. However, risk factors included older age, while one (the third) patient also had several relevant comorbidities (i.e., cardiomyopathy, pacemaker, chronic renal insufficiency and liver cirrhosis). Such patients with severe COVID-19 progression and multiple risk factors (heart disease, severe renal and liver impairment) are generally predisposed for an increased ADR rate. In addition, when several QTc-prolonging drugs are administered concurrently, the risk of QTc time prolongation increases even more due to potential drug-drug interactions. Since the QTc time peak can occur with a delay, patients must be closely monitored by ECG after administration of one and especially several QTc-prolonging drugs. In addition to determining the QTc time before the start of therapy, we also recommend further measurements, namely at the time when peak concentration (Cmax) is reached after the first administration of the implicated drug (Tmax) and after pharmacokinetic steady state is attained, so that a relevant QTc time prolongation can be detected early enough. The QTc time should ideally be monitored until the QTc time returns to pre-treatment values.\n\nIn conclusion, we report three cases of marked QTc prolongation episodes in patients with severe COVID-19 who received LPV/r and HCQ and which were registered by our pharmacovigilance centre. The analysis of individual risk factors suggest that these drugs possibly contributed to the risk of cardiovascular complications in our three patients with severe COVID-19. 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Rautaharju PM Surawicz B Gettes LS Bailey JJ Childers R Deal BJ Gorgels A Hancock EW Josephson M Kligfield P Kors JA Macfarlane P Mason JW Mirvis DM Okin P Pahlm O Herpen Gvan Wagner GS Wellens H American Heart Association Electrocardiography and Arrhythmias CommitteeCouncil on Clinical CardiologyAmerican College of Cardiology FoundationHeart Rhythm Society 2009 AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology J Am Coll Cardiol 53 11 982 991 10.1016/j.jacc.2008.12.014 10.1016/j.jacc.2008.12.014 19281931\n8. The use of the WHO-UMC system for standardised case causality assessment. https://www.who.int/publications/m/item/WHO-causality-assessment 24 May 2021\n9. Del Zompo F De Siena M Ianiro G Gasbarrini A Pompili M Ponziani FR 2020 Prevalence of liver injury and correlation with clinical outcomes in patients with COVID-19: systematic review with meta-analysis Eur Rev Med Pharmacol Sci 24 24 13072 13088 10.26355/eurrev_202012_24215 10.26355/eurrev_202012_24215 33378061\n10. Product Information Kaletra AbbVie®. AbbVie S.A. Switzerland: Cham; 2020. https://compendium.ch/product/1049807-kaletra-filmtabl-200mg-50mg/mpro 10 December 2020\n11. Product Information Plaquenil Sanofi-Aventis®. Sanofi-Aventis (Suisse) S.A. Switzerland: Vernier/GE; 2019. https://compendium.ch/product/15033-plaquenil-filmtabl-200-mg/mpro#MPro7850 10 December 2020\n12. Product Information Erythrocin®. Recordati S.A. Switzerland: Baar; 2016. https://compendium.ch/product/23053-erythrocin-i-v-trockensub-1000-mg/mpro 10 December 2020\n13. Zequn Z Yujia W Dingding Q Jiangfang L 2021 Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel Eur J Pharmacol 893 173813 10.1016/j.ejphar.2020.173813 10.1016/j.ejphar.2020.173813 33345848\n14. Food and Drug Administration HHS 2005 Drug Administration HHS International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability Notice Fed Regist 70 202 61134 61135 16237860\n15. Yap YG Camm AJ 2003 Drug induced QT prolongation and torsades de pointes Heart 89 11 1363 1372 14594906\n16. VigiBase®, Uppsala Monitoring Centre, Sweden, accessed via VigiAccesTMhttp://www.vigiaccess.org/ 2 February 2021\n17. Rendic S Guengerich FP 2020 Metabolism and interactions of chloroquine and hydroxychloroquine with human cytochrome P450 enzymes and drug transporters Curr Drug Metab 21 14 1127 1135 10.2174/1389200221999201208211537 10.2174/1389200221999201208211537 33292107\n18. Wishart DS Feunang YD Guo AC Lo EJ Marcu A Grant JR Sajed T Johnson D Li C Sayeeda Z Assempour N Iynkkaran I Liu Y Maciejewski A Gale N Wilson A Chin L Cummings R Le D Pon A Knox C Wilson M 2018 DrugBank 5.0: a major update to the DrugBank database for 2018 Nucleic Acids Res 46 D1 D1074 D1082 10.1093/nar/gkx1037 10.1093/nar/gkx1037 29126136\n19. Marzolini C Stader F Leuppi-Taegtmeyer A Stoeckle M Battegay M Sendi P 2020 Sex differences in lopinavir concentrations and occurrence of marked QTc prolongation episodes in patients with COVID-19 Drug Saf 10.1007/s40264-020-01025-z 10.1007/s40264-020-01025-z\n\n", "fulltext_license": "CC BY", "issn_linking": "2305-7823", "issue": "2021(2)", "journal": "Global cardiology science & practice", "keywords": null, "medline_ta": "Glob Cardiol Sci Pract", "mesh_terms": null, "nlm_unique_id": "101613130", "other_id": null, "pages": "e202111", "pmc": null, "pmid": "34285902", "pubdate": "2021-06-30", "publication_types": "D016428:Journal Article; D016454:Review", "references": "32641296;33378061;33292107;33245507;14594906;19281931;29126136;32352535;32578156;33264556;33345848;16237860;32942793;33122341", "title": "Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre.", "title_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre" }	[ { "companynumb": "CH-NOVARTISPH-NVSC2022CH098311", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR\\RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Istampoulouoglou I, Zimmermanns B, Grandinett T, Marzolini C, Harings-Kaim A, Koechlin-Lemke S et al. Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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"drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIATEC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20200325", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200325", "drugstartdateformat": "102", "drugstructuredosagenumb": "2.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CO?AMOXI" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT 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CARDIOVASCULAR ADVERSE EFFECTS OF LOPINAVIR/RITONAVIR AND HYDROXYCHLOROQUINE IN COVID?19 PATIENTS: CASES FROM A SINGLE PHARMACOVIGILANCE CENTRE. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2021?.", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CH", "receiptdate": "20210726", "receivedate": "20200424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17705879, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "CH-ABBVIE-20K-151-3392070-00", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 1", "drugenddate": "20200329", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200327", "drugstartdateformat": "102", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAQUENIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021906", "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 1: 2X800/200MG", "drugenddate": "20200331", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200329", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": null, "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200406", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 3", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAQUENIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOCILIZUMAB" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20200402", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200401", "drugstartdateformat": "102", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTEMRA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 2", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAQUENIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.0GR / 0.25MG", "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200402", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAZOBAC" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021906", "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X400/100 MG/DAY", "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200402", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN/CLAVULANIC ACID" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 202003" } }, "primarysource": { "literaturereference": "BASSETTI S, SCHOLZ I, MARZOLINI C, ET.AL.. CARDIOVASCULAR ADVERSE EFFECTS OF LOPINAVIR/RITONAVIR AND HYDROXYCHLOROQUINE IN COVID?19 PATIENTS: CASES FROM A SINGLE PHARMACOVIGILANCE CENTRE. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2021?.", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CH", "receiptdate": "20210724", "receivedate": "20200507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17758709, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CH-LUPIN PHARMACEUTICALS INC.-2022-06692", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210543", "drugbatchnumb": "Unknown", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK (ON DAY 1 AND 2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210543", "drugbatchnumb": "Unknown", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK (ON DAY 3)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 DOSAGE FORM, BID (800/200MG TWO TIMES A DAY ON DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "804", "medicinalproduct": "LOPINAVIR\\RITONAVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 DOSAGE FORM, QD (400/100 MG/DAY FOR 5 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "LOPINAVIR\\RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Istampoulouoglou I, Zimmermanns B, Grandinetti T, Marzolini C, Harings-Kaim A, Koechlin-Lemke S, et al. Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2021;11:1-7", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20220502", "receivedate": "20220502", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20775420, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" }, { "companynumb": "CH-LUPIN PHARMACEUTICALS INC.-2022-06693", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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{ "abstract": "A chronic dialysis patient developed persistent bacteremia as a result of infection with Enterococcus faecium. During the patient's illness, resistance to ampicillin, gentamicin, vancomycin, and teicoplanin developed. Despite arteriovenous (AV) graft removal and an extensive but inconclusive search for the source of the infection, bacteremia persisted. On autopsy, the patient was found to have had aortic-valve endocarditis. Endocarditis is a well-known complication in dialysis patients. Multidrug-resistant organisms are becoming more prevalent in hospitalized patients as well. Risk factors for the development of endocarditis in dialysis patients include catheters, AV grafts, and calcific valvular disease, all in conjunction with frequent access to the circulation. Avoidance of temporary catheter use by prompt placement of AV fistulas or grafts and consideration of their early use, the meticulous care of catheters once in place, and treatment of the nasal carriage of Staphylococcus aureus may lower the incidence of bacteremia and therefore endocarditis in dialysis patients. The removal of infected catheters and/or AV grafts if prompt clearing of the blood with antibiotics does not occur is the next step, followed by valve replacement in selected cases. The routine use of vancomycin in the dialysis population should be reevaluated in light of the development of high-level antibiotic-resistant organisms.", "affiliations": "Department of Medicine, George Washington University Medical Center, Washington, DC, USA.", "authors": "Vijayvargiya|R|R|;Veis|J H|JH|", "chemical_list": "D005839:Gentamicins; D002939:Ciprofloxacin; D017334:Teicoplanin; D014640:Vancomycin; D000667:Ampicillin", "country": "United States", "delete": false, "doi": "10.1681/ASN.V74536", "fulltext": null, "fulltext_license": null, "issn_linking": "1046-6673", "issue": "7(4)", "journal": "Journal of the American Society of Nephrology : JASN", "keywords": null, "medline_ta": "J Am Soc Nephrol", "mesh_terms": "D000667:Ampicillin; D016470:Bacteremia; D002939:Ciprofloxacin; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial; D016984:Enterococcus faecium; D005839:Gentamicins; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D017334:Teicoplanin; D014640:Vancomycin", "nlm_unique_id": "9013836", "other_id": null, "pages": "536-42", "pmc": null, "pmid": "8724886", "pubdate": "1996-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Antibiotic-resistant endocarditis in a hemodialysis patient.", "title_normalized": "antibiotic resistant endocarditis in a hemodialysis patient" }

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ANTIBIOTIC?RESISTANT ENDOCARDITIS IN A HEMODIALYSIS PATIENT. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY: JASN. 1996?7 (4):536?542", "literaturereference_normalized": "antibiotic resistant endocarditis in a hemodialysis patient", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180913", "receivedate": "20180911", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15370669, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]

{ "abstract": "Drug interactions involving human immunodeficiency virus protease inhibitors are common due to their inhibition of the cytochrome P450 3A4 isoenzyme. We describe the case of an HIV-infected patient treated with ritonavir-boosted darunavir who developed cushingoid features following an intra-articular injection of triamcinolone acetate. We review the probable mechanism for this interaction and describe similar cases of Cushing syndrome in patients receiving concomitant ritonavir and triamcinolone.", "affiliations": "Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.", "authors": "Hall|Jill J|JJ|;Hughes|Christine A|CA|;Foisy|Michelle M|MM|;Houston|Stan|S|;Shafran|Stephen|S|", "chemical_list": "D005938:Glucocorticoids; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D014221:Triamcinolone; D019438:Ritonavir; D000069454:Darunavir", "country": "England", "delete": false, "doi": "10.1177/0956462413480723", "fulltext": null, "fulltext_license": null, "issn_linking": "0956-4624", "issue": "24(9)", "journal": "International journal of STD & AIDS", "keywords": "AIDS; Cushing syndrome; HIV; HIV protease inhibitors; antiretrovirals; cobicistat; corticosteroids; drug interactions; ritonavir; toxicity; triamcinolone", "medline_ta": "Int J STD AIDS", "mesh_terms": "D003480:Cushing Syndrome; D000069454:Darunavir; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D007049:Iatrogenic Disease; D007270:Injections, Intra-Articular; D008875:Middle Aged; D019438:Ritonavir; D020069:Shoulder Pain; D013449:Sulfonamides; D016896:Treatment Outcome; D014221:Triamcinolone", "nlm_unique_id": "9007917", "other_id": null, "pages": "748-52", "pmc": null, "pmid": "23970582", "pubdate": "2013-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir.", "title_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir" }

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IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. 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IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. 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IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. 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IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714610, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10659", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR/RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, STAT, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714615, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-10663", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, ONCE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR/EMTRICITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 2 DOSES, INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DARUNAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARUNAVIR/RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HALL JJ, HUGHES CA, FOISY MM, HOUSTON S, ET AL.. IATROGENIC CUSHING SYNDROME AFTER INTRA-ARTICULAR TRIAMCINOLONE IN A PATIENT RECEIVING RITONAVIR-BOOSTED DARUNAVIR. INTERNATIONAL JOURNAL OF STD + AIDS.. 2013?24(9):748-756", "literaturereference_normalized": "iatrogenic cushing syndrome after intra articular triamcinolone in a patient receiving ritonavir boosted darunavir", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "GB", "receiptdate": "20181212", "receivedate": "20181212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15714613, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "A 32-year-old woman (148 cm, 59 kg, gravida 2, para 2) with quadruplet pregnancy was admitted to our hospital for the threatened preterm labor at 23 weeks and 2 days of gestation. She was treated with ritodrine, magnesium sulfate and nifedipine to maintain tocolysis. Betamethasone was administered to accelerate fetal lung maturity. After ritodrine dose was increased at 23 weeks and 5 days of gestation, she developed dyspnea with desaturation. Acute pulmonary edema was revealed on chest X-ray. The decision was made to proceed with emergency cesarean delivery. On arrival at the operating room, the blood pressure was 123/53 mmHg, heart rate 111 beats x min(-1), and oxygen saturation (SpO2) 84% with supplemental oxygen 15 l x min(-1) via a reserved face mask. Noninvasive positive pressure ventilation (NPPV) was initiated with S/T mode (FIO2 1.0, inspiratory positive airway pressure 10 cmH2O, expiratory positive airway pressure 6 cmH2O). The dyspnea was improved with her SpO2 100%. Spinal anesthesia was performed at L 34 using 2.5 ml of 0.5% bupivacaine and 100 microg morphine. Throughout the operation (operation time 44 minutes), she did not develop dyspnea under NPPV. NPPV was discontinued after the operation. Her SpO2 declined, and pulmonary edema on chest X-ray was exacerbated. She was transferred to the intensive care unit and NPPV was continued for 22 hours after the operation. She was discharged from the intensive care unit on the next day and was discharged from the hospital on the 6th postoperative day.", "affiliations": null, "authors": "Fujita|Naoko|N|;Tachibana|Kazuya|K|;Takeuchi|Muneyuki|M|;Kinouchi|Keiko|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0021-4892", "issue": "63(5)", "journal": "Masui. The Japanese journal of anesthesiology", "keywords": null, "medline_ta": "Masui", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000767:Anesthesia, Epidural; D002585:Cesarean Section; D004630:Emergencies; D005260:Female; D006801:Humans; D011175:Positive-Pressure Respiration; D011247:Pregnancy; D011654:Pulmonary Edema", "nlm_unique_id": "0413707", "other_id": null, "pages": "557-60", "pmc": null, "pmid": "24864580", "pubdate": "2014-05", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema.", "title_normalized": "successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema" }

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SUCCESSFUL PERIOPERATIVE USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION IN A PREGNANT WOMAN WITH ACUTE PULMONARY EDEMA. MASUI. 2014;MAY;63(5):557-60", "literaturereference_normalized": "successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170714", "receivedate": "20170714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13755686, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "JP-BAYER-2014-086191", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MAGNESIUM SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CONTRACTIONS DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAGNESIUM SULFATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITODRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 ?G/MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CONTRACTIONS DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITODRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL THERAPY TO ENHANCE FOETAL LUNG MATURITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020198", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TOCOLYSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020198", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CONTRACTIONS DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITODRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 ?G/MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CONTRACTIONS DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITODRINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITODRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "66 MG/MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CONTRACTIONS DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITODRINE" } ], "patientagegroup": "5", "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "59", "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Oxygen saturation decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Acute pulmonary oedema", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FUJITA N, TACHIBANA K, TAKEUCHI M, KINOUCHI K. SUCCESSFUL PERIOPERATIVE USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION IN A PREGNANT WOMAN WITH ACUTE PULMONARY EDEMA. MASUI. 2014;63 (5):557-560", "literaturereference_normalized": "successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20140701", "receivedate": "20140617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10242313, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]

{ "abstract": "The complexity of managing children with chronic disease has led to an increase in the use of long-term warfarin therapy. Time in therapeutic range (TTR) is the preferred method for determining efficacy and stability of warfarin management. This study aimed to determine the TTR achievement and incidence of adverse events among pediatric warfarin patients managed by an anticoagulation clinic over 12 months and to compare TTR achievement between patients self-testing (PST) at home and those monitored using routine methods. International normalized ratio (INR) results reported for 2012 for children currently having their warfarin therapy managed by a dedicated pediatric anticoagulation clinic were analyzed. Warfarin-related adverse events were recorded. A total of 164 patients were included. In total, 93 children performed PST and 71 children tested their INR at a hospital or pathology service. TTR achievement for the cohort was 67.1% (95% confidence interval, 64.4-69.7). A total of 69.2% of INR tests conducted at home were within the TTR compared with 64.3% of INR tests conducted at a hospital or pathology service (P=0.07). One major bleeding event occurred and there was 1 thrombotic episode. PST demonstrated noninferior warfarin stability compared with routine methods. Routine outcome evaluation of pediatric anticoagulation management within single institutions is necessary to confirm the success of such programs.", "affiliations": "Departments of *Nursing §Paediatrics, The University of Melbourne †Haematology Research, Murdoch Childrens Research Institute Departments of ‡Clinical Haematology ∥Nursing Research, The Royal Children's Hospital, Melbourne, Australia.", "authors": "Jones|Sophie|S|;McLoughlin|Siobhan|S|;Piovesan|Dana|D|;Savoia|Helen|H|;Monagle|Paul|P|;Newall|Fiona|F|", "chemical_list": "D000925:Anticoagulants; D014859:Warfarin", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000502", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "38(3)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D001777:Blood Coagulation; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019934:International Normalized Ratio; D008297:Male; D017063:Outcome Assessment, Health Care; D010044:Outpatient Clinics, Hospital; D012648:Self Care; D014859:Warfarin; D055815:Young Adult", "nlm_unique_id": "9505928", "other_id": null, "pages": "216-20", "pmc": null, "pmid": "26808370", "pubdate": "2016-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Safety and Efficacy Outcomes of Home and Hospital Warfarin Management Within a Pediatric Anticoagulation Clinic.", "title_normalized": "safety and efficacy outcomes of home and hospital warfarin management within a pediatric anticoagulation clinic" }

[ { "companynumb": "AU-MYLANLABS-2016M1019339", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "THERAPEUTIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intracardiac thrombus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JONES S, MCLOUGHLIN S, PIOVESAN D, SAVOIA H, MONAGLE P, NEWALL F. SAFETY AND EFFICACY OUTCOMES OF HOME AND HOSPITAL WARFARIN MANAGEMENT WITHIN A PEDIATRIC ANTICOAGULATION CLINIC. J-PEDIATR-HEMATOL-ONCOL 2016;38(3):216-220.", "literaturereference_normalized": "safety and efficacy outcomes of home and hospital warfarin management within a pediatric anticoagulation clinic", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160511", "receivedate": "20160511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12355181, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "OBJECTIVE\nTo compare the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in less mature preterm infants.\n\n\nMETHODS\nProspective, randomised controlled study.\n\n\nMETHODS\nTertiary neonatal intensive care unit.\n\n\nMETHODS\nThe study enrolled 80 preterm infants with gestational age ≤28 weeks, birth weight <1000 g, postnatal age 48 to 96 h, and had echocardiographically confirmed significant PDA. Seventy extremely low birthweight (ELBW) preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h.\n\n\nMETHODS\nThe success rate and the safety of the drugs in ELBW preterm infants were the major outcomes.\n\n\nRESULTS\nPDA closure rate was significantly higher with oral ibuprofen (83.3% vs 61.7%) after the first course of the treatment (p=0.04). Although the primary closure rate was marginally higher in the oral ibuprofen group, the need for a second course of ibuprofen during the whole hospitalisation was similar between groups: 11 of 36 in oral versus 15 of 34 in intravenous groups (p=0.24) because of a higher reopening rate in the oral group. In addition to no increase in side effects with oral ibuprofen use, the need for postnatal steroid use for chronic lung disease was significantly lower in oral ibuprofen group (p=0.001).\n\n\nCONCLUSIONS\nOral ibuprofen is as effective as intravenous ibuprofen for PDA closure even in ELBW infants.", "affiliations": "Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. omererdeve@yahoo.com", "authors": "Erdeve|Omer|O|;Yurttutan|Sadik|S|;Altug|Nahide|N|;Ozdemir|Ramazan|R|;Gokmen|Tulin|T|;Dilmen|Ugur|U|;Oguz|Serife Suna|SS|;Uras|Nurdan|N|", "chemical_list": "D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen", "country": "England", "delete": false, "doi": "10.1136/archdischild-2011-300532", "fulltext": null, "fulltext_license": null, "issn_linking": "1359-2998", "issue": "97(4)", "journal": "Archives of disease in childhood. Fetal and neonatal edition", "keywords": null, "medline_ta": "Arch Dis Child Fetal Neonatal Ed", "mesh_terms": "D000284:Administration, Oral; D001724:Birth Weight; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D005260:Female; D005865:Gestational Age; D006801:Humans; D007052:Ibuprofen; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D015931:Intensive Care, Neonatal; D008171:Lung Diseases; D008297:Male; D016896:Treatment Outcome", "nlm_unique_id": "9501297", "other_id": null, "pages": "F279-83", "pmc": null, "pmid": "22147286", "pubdate": "2012-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": null, "title": "Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants.", "title_normalized": "oral versus intravenous ibuprofen for patent ductus arteriosus closure a randomised controlled trial in extremely low birthweight infants" }

[ { "companynumb": "TR-STRIDES ARCOLAB LIMITED-2016SP016820", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, AT 48 HOURS THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/KG, THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PATENT DUCTUS ARTERIOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, AT 24 HOURS THROUGH OROGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERDEVE O, YURTTUTAN S, ALTUG N, OZDEMIR R, GOKMEN T, DILMEN U, OGUZ SS, URAS N.. ORAL VERSUS INTRAVENOUS IBUPROFEN FOR PATENT DUCTUS ARTERIOSUS CLOSURE: A RANDOMISED CONTROLLED TRIAL IN EXTREMELY LOW BIRTHWEIGHT INFANTS.. ARCH DIS CHILD FETAL NEONATAL ED.. 2012;97(4):F279-83", "literaturereference_normalized": "oral versus intravenous ibuprofen for patent ductus arteriosus closure a randomised controlled trial in extremely low birthweight infants", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20161103", "receivedate": "20161103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12905306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "Exposure of the fetus to indomethacin by administration of the drug to the mother may cause many side effects, including premature closure of the ductus arteriosus. Hypoxia is a predisposing factor for premature ductal closure and often occurs after maternal indomethacin therapy. We present two sets of monozygotic twins with twin-to-twin transfusion, where in utero ductal closure occurred in the donor twin while the recipient twin appeared unaffected. This selective closure of the ductus arteriosus suggests that the affected twin was predisposed to hypoxia and thus was more susceptible to ductal closure in response to indomethacin exposure.", "affiliations": "Children's Healthcare of Atlanta at Egleston, Department of Pathology, Emory University, Atlanta, Georgia 30322, USA. bshehat@emory.edu", "authors": "Shehata|Bahig M|BM|;Bare|Jessica B|JB|;Denton|Tiffany D|TD|;Habib|Maria N|MN|;Black|Jennifer O|JO|", "chemical_list": "D015149:Tocolytic Agents; D007213:Indomethacin", "country": "England", "delete": false, "doi": "10.1080/15513810600908354", "fulltext": null, "fulltext_license": null, "issn_linking": "1551-3815", "issue": "25(3)", "journal": "Fetal and pediatric pathology", "keywords": null, "medline_ta": "Fetal Pediatr Pathol", "mesh_terms": "D000328:Adult; D000013:Congenital Abnormalities; D004373:Ductus Arteriosus; D017809:Fatal Outcome; D005260:Female; D005330:Fetofetal Transfusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D000860:Hypoxia; D007213:Indomethacin; D007231:Infant, Newborn; D006831:Polyhydramnios; D011247:Pregnancy; D047928:Premature Birth; D015149:Tocolytic Agents; D014430:Twins, Monozygotic", "nlm_unique_id": "101230972", "other_id": null, "pages": "151-7", "pmc": null, "pmid": "17060191", "pubdate": "2006", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Premature closure of the ductus arteriosus: variable response among monozygotic twins after in utero exposure to indomethacin.", "title_normalized": "premature closure of the ductus arteriosus variable response among monozygotic twins after in utero exposure to indomethacin" }

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{ "abstract": "Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder primarily caused by GATA3 haploinsufficiency and is challenging to diagnose in early childhood. We report a Japanese family with HDR syndrome and congenital choanal atresia. The 6-year-old female proband was diagnosed with epilepsy at the age of three. Under carbamazepine monotherapy, the patient presented hypoparathyroidism accompanied by severe hypocalcemia. Subsequently, renal ultrasound analysis revealed bilateral multicystic dysplastic kidneys. Because she had difficulty hearing, we sequenced GATA3 and determined that she had a c.708_709insC (p.Ser237Glnfs*66) allelic variant in exon 3. As a result, we found a family of this disease. Each family member, including her grandfather, mother, and two siblings, had HDR syndrome of varying clinical penetrance. We found a craniofacial anomaly, congenital choanal atresia, which was inherited as an autosomal dominant trait. Hypocalcemia coupled with vitamin D deficiency, triggered by carbamazepine treatment, ultimately revealed the proband's childhood- onset HDR syndrome. Pure-tone audiometry revealed different severities of deafness as well as the progression of sensory hearing loss. However, auditory brainstem response for hearing screening is probably insufficient for ascertaining HDR syndrome in the early stages of life. We presented new clinical clues to diagnose the HDR syndrome.", "affiliations": "National Hospital Organization Kyoto Medical Center, Department of Pediatrics, Kyoto, Japan. Electronic address: mkita@kyotolan.hosp.go.jp.;National Hospital Organization Kyoto Medical Center, Department of Neurology, Kyoto, Japan.;Shizuoka Prefectural Hospital Organization, Department of Medical Genetics, Shizuoka, Japan.", "authors": "Kita|Makoto|M|;Kuwata|Yasuhiro|Y|;Usui|Takeshi|T|", "chemical_list": "D000927:Anticonvulsants; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D002220:Carbamazepine", "country": "Netherlands", "delete": false, "doi": "10.1016/j.anl.2018.10.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0385-8146", "issue": "46(5)", "journal": "Auris, nasus, larynx", "keywords": "Congenital choanal atresia; GATA binding protein 3; Hypoparathyroidism-deafness-renal dysplasia; Sensorineural hearing loss", "medline_ta": "Auris Nasus Larynx", "mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001301:Audiometry, Pure-Tone; D002220:Carbamazepine; D002648:Child; D002754:Choanal Atresia; D004827:Epilepsy; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D050990:GATA3 Transcription Factor; D000066502:Grandparents; D057895:Haploinsufficiency; D006319:Hearing Loss, Sensorineural; D006801:Humans; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009035:Mothers; D015997:Neonatal Screening; D009401:Nephrosis; D010375:Pedigree; D035781:Siblings; D014057:Tomography, X-Ray Computed; D014808:Vitamin D Deficiency", "nlm_unique_id": "7708170", "other_id": null, "pages": "808-812", "pmc": null, "pmid": "30396722", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Familial congenital choanal atresia with GATA3 associated hypoparathyroidism-deafness-renal dysplasia syndrome unidentified on auditory brainstem response.", "title_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response" }

[ { "companynumb": "JP-JUBILANT CADISTA PHARMACEUTICALS-2018JUB00475", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071940", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitamin D deficiency", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Primary hypoparathyroidism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tetany", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI T. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2018", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181126", "receivedate": "20181126", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15657169, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PHHY2018JP159384", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016608", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperphosphataemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI T. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2018?46(5):808-12", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190827", "receivedate": "20181123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15649792, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PHHY2019JP197693", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "016608", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperphosphataemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITA M, KUWATA Y, USUI. FAMILIAL CONGENITAL CHOANAL ATRESIA WITH GATA3 ASSOCIATED HYPOPARATHYROIDISM-DEAFNESS-RENAL DYSPLASIA SYNDROME UNIDENTIFIED ON AUDITORY BRAINSTEM RESPONSE. AURIS NASUS LARYNX. 2019?46:808-12", "literaturereference_normalized": "familial congenital choanal atresia with gata3 associated hypoparathyroidism deafness renal dysplasia syndrome unidentified on auditory brainstem response", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190827", "receivedate": "20190827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16748190, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "Zolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction. Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential, but several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal.\nA 32-year-old unmarried woman suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. She began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days the dose increased up to 100 mg per day. In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Post-ictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in the patient.\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects.", "affiliations": "Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran.;Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran.", "authors": "Hadinezhad|Pezhman|P|;Hosseini|Seyed Hamzeh|SH|", "chemical_list": null, "country": "Iran", "delete": false, "doi": "10.22088/cjim.12.0.376", "fulltext": "\n==== Front\nCaspian J Intern Med\nCaspian J Intern Med\nCJIM\nCaspian Journal of Internal Medicine\n2008-6164\n2008-6172\nBabol University of Medical Sciences Babol, Iran\n\n10.22088/cjim.12.0.376\nCase Report\nZolpidem withdrawal seizure in an Iranian young woman: A case presentation\nHadinezhad Pezhman MD 1*\nHosseini Seyed Hamzeh MD 2\n1 Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran\n2 Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran\n* Correspondence: Pezhman Hadinezhad, Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran. E-mail: pezhman.hadinezhad@gmail.com, Tel: 0098 1133203637, Fax: 0098 1133203637\n2021\n12 Suppl 2 S376S378\n3 6 2019\n8 12 2019\n30 12 2019\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground:\n\nZolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction. Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential, but several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal.\n\nCase presentation:\n\nA 32-year-old unmarried woman suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. She began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days the dose increased up to 100 mg per day. In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Post-ictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in the patient.\n\nConclusion:\n\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects.\n\nKey Words\n\nZolpidem\nWithdrawal\nSeizure\nCase report\n==== Body\npmcLong-term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short-term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life (1). Zolpidem is a non-benzodiazepine drug, approved by FDA for sleep induction (2) and a short acting hypnotic drug belonging to imidazopyridine family (3). It produces its hypnotic effects via the GABA-A benzodiazepine receptor complex, and binds preferentially to those receptors containing the alpha-1 subunit (4, 5). Zolpidem is thought to be a safer drug than benzodiazepines (BZD) because of no evidence of abuse or dependence potential (6). In comparison with benzodiazepines,this mechanism is thought to reduce liability to induce dependence (7). Earlier it was considered to be a safer hypnotic than benzodiazepines due to its lesser potentiality to cause abuse (8). But several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal (9). Here we report a case of seizure related to withdrawal of zolpidem after long-term use in high dosage in Iran.\n\nCase presentation\n\nA 32-years-old unmarried woman who had no history of any medical disorder or head trauma and no family history of epilepsy suffering from major depressive disorder had been taking zolpidem for insomnia for more than 1 year. Since one year ago after her brother’s sudden death, she began to take zolpidem alone without mixing other kinds of hypnotics, and 50 mg of zolpidem used to be initially effective in treating her insomnia. In some days, the dose increased up to 100 mg per day About 9 months later, she refers to a psychiatrist because of depression, anhedonia, fatigue, hopelessness and decreased appetite and the psychiatrist prescribed sertraline 50 mg once a day with diagnosis of major depressive disorder, the patient had taken the drugs with no problem for the past 3 months until than she was infected with herpes simplex virus and her doctor prescribed acyclovir 400 mg each 6 hours (1600 mg a day). In the end, she had to discontinue zolpidem abruptly because she could not afford it anymore. After 2 days, she suddenly showed facial spasm, mouth opening, tonic-clonic seizure, and loss of consciousness for about 1-2 minutes. Postictal confusion with clouded consciousness, psycho-motor retardation, persisted in 1 day. So she referred to her psychiatrist and a consultation with a neurologist had been requested by the psychiatrist. The neurological examinations were normal and EEG in wakefulness revealed intermittent, generalized, diffused alpha wave and diffused sharp waves, and suggested seizure waves in patient. As well as we use Naranjo scale for estimating the probability of relationship between seizure and zolpidem withdrawal, the patient score was 10, hence other etiologies or drugs either idiopathic causes were ruled out. After a series of laboratory tests and other examinations, no other etiologies could be identified in MRI. After 4 weeks follow-up, she consumed 5 mg zolpidem at bed time and she had no further seizure attacks and her postictal confusion resolved gradually 1 day after seizure occurred.\n\nDiscussion\n\nDuring the last decade, zolpidem (a non BZD hypnotic drug) was considered a new way for the treatment of patients with insomnia as it was suggested that it has the efficacy of BZDs for insomnia but without many side effects (10). It was suggested that zolpidem lacked muscle relaxant, anticonvulsant and anxiolytic properties and poor potential for abuse or dependence (11). GABA-A receptors include α1, α2, α3, α4, and α5 subunits receptors. The α1 subunit involves in sleeping mechanisms and α2 subunit contributes to anxiolytic action. BZDs have nonselective affinity to GABA-A subunits (12). A hypothesis about zolpidem withdrawal is long-term supra therapeutic doses saturation of the lower-affinity α2, α3 and α5 subunits on GABA-A receptors along with α1 subunits (13). Therefore, abrupt discontinuation of high doses would produce withdrawal symptoms such as anxiety, tremor, palpitation, or seizure (similar to BZDs withdrawal). Withdrawal symptoms of zolpidem were reported in less than 1% of subjects appearing within 48 hours of discontinuation (14). One of the probable factors associated with adverse effects of zolpidem is gender. Women have been found to have a significantly higher serum zolpidem concentration than men at equivalent dosage (15).\n\nSome studies showed that zolpidem withdrawal seizures occurred in higher doses than our case. In Haji Seyed Javadi et al.’s case presentation of a 30-year-old unmarried Iranian woman with dysthymic disorder and chronic insomnia was treated with zolpidem irregularly. She started to use zolpidem with 5mg per day irregularly since a year ago but augmented its daily dosage gradually to 100 to 150 mg per day in divided doses. After a period of 16 hours without taking zolpidem she developed a withdrawal syndrome, with generalized tonic-clonic seizures for two times. She was managed with supportive care and recovered completely (16). In our report, the patient consumed lower dose of zolpidem versus the current study. In other case presentations, Wang and et al. reported 2 cases of zolpidem withdrawal seizures and the result showed that potential of zolpidem dependence and withdrawal seizure are also present in the Asian population (17). According to these studies, gender is one of the susceptibility factors associated with adverse effects of zolpidem. Women had been found to have a significantly higher serum zolpidem concentration than men at equivalent dosage and in the end, ethnic differences have been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6 (18, 19). According to other case reports and studies and our case, zolpidem, soon after sudden discontinuation, causes withdrawal symptoms including insomnia, anxiety and epileptic attack, especially at high doses and long-term use. There have been several reports describing neuropsychiatric reactions such as visual hallucinations/sensory distortion, delirium, amnesia, sleepwalking/somnambulism, and nocturnal eating associated with zolpidem use (20). We suggest physicians to pay more attention to the potential of zolpidem to create dependence and withdrawal seizure. Besides, they should always keep its effects in their mind and subtilize during prescription of zolpidem for any patients and at any doses, especially for those with a previous history of drug or substance abuse and at high doses. However, this is a case study and it needs further studies to conclude about adverse effects of zolpidem.\n\nOur case suggested that the potential of zolpidem dependence and withdrawal seizure are also present in the Iranian population. The female-gender, high dosage and long-term use of zolpidem might be risk factors for the development of adverse effects. It warrants further investigation whether there is ethnic variation for the liability of zolpidem dependence. Nevertheless, worldwide clinicians should pay attention to the risk of withdrawal seizure related to this agent, especially at high doses.\n\nAcknowledgments\n\nWe are also grateful to each and every colleague of ours for their assistance and all people who moderated this paper,thus has improved the manuscript significantly.\n\nConflict of Interests:\n\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n\n1 Lahteenmaki R Neuvonen PJ Puustinen J Withdrawal from long-term use of zopiclone, zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia Basic Clin Pharmacol Toxicol 2019 124 330 40 30295409\n2 Sanger DJ Depoortere H The pharmacology and mechanism of action of zolpidem CNS Drug Rev 1998 4 323 40 29200233\n3 Aragona M Abuse, dependence, and epileptic seizures after zolpidem withdrawal: review and case report Clin Neuropharmacol 2000 23 281 3 11154097\n4 Chang CC Wang WF High-dose zolpidem withdrawal seizure in a patient with spinocerebellar ataxia Prim Care Companion CNS Disord 2011 13 10l01114\n5 Chiaro G Castelnovo A Bianco G Maffei P Manconi M Severe chronic abuse of zolpidem in refractory insomnia J Clin Sleep Med 2018 14 1257 9 29991431\n6 Holm KJ Goa KL Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia Drugs 2000 59 865 89 10804040\n7 Pitchot W Ansseau M Zolpidem dependence and withdrawal seizure Revue Med Liege 2009 64 407 8\n8 Boulanger-Rostowsky L Fayet H Benmoussa N Ferrandi J Dependence on zolpidem: a report of two cases L'Encephale 04 30 153 5\n9 Cubała WJ Landowski J Seizure following sudden zolpidem withdrawal Prog Neuropsychopharmacol Biol Psychiatry 2007 31 539 40 16950552\n10 Ohshima H Kotorii N Takii M Polysomnographic sleep disturbances due to high-dose zolpidem use: a case report J Clin Sleep Med 2018 14 1949 52 30373692\n11 Salva P Costa J Clinical pharmacokinetics and pharmacodynamics of zolpidem Therapeutic implications Clin Pharmacokinet 1995 29 142 53 8521677\n12 McKernan RM Rosahl TW Reynolds DS Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype Nature Neurosci 2000 3 587 92 10816315\n13 Liappas IA Malitas PN Dimopoulos NP Zolpidem dependence case series: possible neurobiological mechanisms and clinical management J Psychopharmacol 2003 17 131 5 12680751\n14 Toner LC Tsambiras BM Catalano G Catalano MC Cooper DS Central nervous system side effects associated with zolpidem treatment Clin Neuropharmacol 2000 23 54 8 10682233\n15 Cubała WJ Landowski J Wichowicz HM Zolpidem abuse, dependence and withdrawal syndrome: sex as susceptibility factor for adverse effects Br J Clin Pharmacol 2008 65 444 5 17875189\n16 Haji Seyed Javadi SA Hajiali F Nassiri-Asl M Zolpidem dependency and withdrawal seizure: a case report study Iranian Red Crescent Med J 2014 16 e19926\n17 Wang LJ Ree SC Chu CL Juang YY Zolpidem dependence and withdrawal seizure--report of two cases Psychiatr Danub 2011 23 76 8 21448102\n18 Anthony M Berg MJ Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I J Womens Health Gend Based Med 2002 11 601 15 12396893\n19 Afilal D Basselam MA Brakez Z Genetic polymorphism of drug-metabolizing enzymes CYP2C9 and CYP2C19 in Moroccan population Genet Test Mole Biomarkers 2017 21 298 304\n20 Inagaki T Miyaoka T Tsuji S Adverse reactions to zolpidem: case reports and a review of the literature Prim Care Companion J Clin Psychiatry 2010 12 09r00849\n\n", "fulltext_license": "CC BY", "issn_linking": "2008-6164", "issue": "12(Suppl 2)", "journal": "Caspian journal of internal medicine", "keywords": "Case report; Seizure; Withdrawal; Zolpidem", "medline_ta": "Caspian J Intern Med", "mesh_terms": null, "nlm_unique_id": "101523876", "other_id": null, "pages": "S376-S378", "pmc": null, "pmid": "34760086", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "25763219;21448102;17875189;11154097;30295409;8521677;12396893;16950552;28282224;10804040;30373692;10682233;21977371;19777922;12680751;10816315;15107718;21494350;29991431;29200233", "title": "Zolpidem withdrawal seizure in an Iranian young woman: A case presentation.", "title_normalized": "zolpidem withdrawal seizure in an iranian young woman a case presentation" }

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{ "abstract": "Narcolepsy-type 1 is a neurological sleep-disorder caused by a selective loss of hypothalamic orexin/hypocretin-producing neurons whose underlying mechanism is considered to be immune-mediated. We report the case of a 16 year-old girl with excessive daytime sleepiness, hypnagogic/hypnopompic hallucinations and cataplexy, fulfilling narcolepsy-type 1 diagnostic criteria. She was HLA-DQB1*06:02/DQA1*01:02 positive. CSF analysis demonstrated positive IgG oligoclonal bands, pleocytosis and hypocretin-1 below detection limit. Other autoimmune processes were excluded, including autoimmune encephalitis. After treatment with intravenous immunoglobulins sleep-related hallucinations transiently improved for a month. This case's CSF inflammatory findings support the role of neuroinflammation in narcolepsy-type 1 development in genetically predisposed patients.", "affiliations": "Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain. Electronic address: ana.morenoestebanez@osakidetza.eus.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurophysiology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.;Neurology Department, Cruces University Hospital, Plaza Cruces S/N, 48903 Barakaldo, Basque Country, Spain.", "authors": "Moreno-Estébanez|Ana|A|;Bilbao Villabeitia|Iker|I|;Echeverria Guibert|Teresa|T|;Mendibe Bilbao|Mar|M|;Boyero Durán|Sabas|S|;Cabral Martínez|Laura|L|;González-Pinto|Tirso|T|;Agirre Beitia|Garazi|G|;González Eizaguirre|Amaia|A|;Rodríguez-Antigüedad|Alfredo|A|", "chemical_list": "D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; D043025:Oligoclonal Bands", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jneuroim.2019.577111", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-5728", "issue": "339()", "journal": "Journal of neuroimmunology", "keywords": "Autoimmune diseases; Narcolepsy", "medline_ta": "J Neuroimmunol", "mesh_terms": "D000293:Adolescent; D015415:Biomarkers; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007964:Leukocytosis; D009290:Narcolepsy; D043025:Oligoclonal Bands", "nlm_unique_id": "8109498", "other_id": null, "pages": "577111", "pmc": null, "pmid": "31756639", "pubdate": "2020-02-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Positive oligoclonal bands and CSF pleocytosis in narcolepsy type 1: A case report supporting the immune-mediated hypothesis.", "title_normalized": "positive oligoclonal bands and csf pleocytosis in narcolepsy type 1 a case report supporting the immune mediated hypothesis" }

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{ "abstract": "Portopulmonary hypertension is a rare but serious complication of portal hypertension or portosystemic shunting. Portopulmonary hypertension is an indication for liver transplantation or shunt closure. However, liver transplantation is contraindicated in patients with severe pulmonary arterial hypertension. Reported mortality rates are high in children with portopulmonary hypertension and there are scarce recommendations on its management. Our aim was to report on our real-world experience of managing portopulmonary hypertension in a specialised centre. We describe a series of 6 children with portopulmonary hypertension. Their median age at diagnosis was 13 years (range 10-15). The underlying liver conditions were cirrhosis of unknown origin (1), congenital portocaval shunts (3), biliary atresia (1), and portal vein cavernoma with surgical mesenterico-caval shunt (1). Median mean pulmonary arterial pressure was 47 mmHg (range 32-70), and median pulmonary vascular resistance was 6.6 Wood units (range 4.3-15.4). All patients except one were treated with a combination of pulmonary arterial hypertension-specific therapy (phosphodiesterase type 5 inhibitors and/or endothelin receptor antagonists and/or prostacyclin analogues). Three patients then benefited from shunt closure and the others underwent liver transplantation. Five patients showed improvement or stabilisation of pulmonary arterial hypertension with no deaths after a mean follow-up of 39 months. Based on our limited experience, early and aggressive treatment with a combination of pulmonary arterial hypertension-specific therapy significantly improves patients' haemodynamic profile and enables the performance of liver transplantation and shunt closure with satisfactory outcomes.", "affiliations": "Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland. Electronic address: Raphael.Joye@hcuge.ch.;Division of Pneumology, University Hospitals of Geneva, Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.;Swiss Pediatric Liver Center, University Center of Pediatric Surgery of Western Switzerland, Children's University Hospital, Geneva, Switzerland.;Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland; Division of Radiology, University Hospitals of Geneva, Geneva, Switzerland.;Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland; Division of Radiology, University Hospitals of Geneva, Geneva, Switzerland.;Swiss Pediatric Liver Center, Pediatric Gastroenterology, Hepatology and Nutrition Unit, Children's University Hospital, Geneva, Switzerland.;Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.", "authors": "Joye|Raphael|R|;Lador|Frédéric|F|;Aggoun|Yacine|Y|;Farhat|Nesrine|N|;Wacker|Julie|J|;Wildhaber|Barbara Elisabeth|BE|;Vallée|Jean-Paul|JP|;Hachulla|Anne-Lise|AL|;McLin|Valérie Anne|VA|;Beghetti|Maurice|M|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jhep.2020.11.039", "fulltext": null, "fulltext_license": null, "issn_linking": "0168-8278", "issue": "74(3)", "journal": "Journal of hepatology", "keywords": "Liver transplantation; Medical treatment; Paediatrics; Portal hypertension; Portosystemic shunts; Pulmonary arterial hypertension", "medline_ta": "J Hepatol", "mesh_terms": null, "nlm_unique_id": "8503886", "other_id": null, "pages": "742-747", "pmc": null, "pmid": "33276028", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Outcome of paediatric portopulmonary hypertension in the modern management era: A case report of 6 patients.", "title_normalized": "outcome of paediatric portopulmonary hypertension in the modern management era a case report of 6 patients" }

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{ "abstract": "Despite well-established cardiovascular benefits, statins have been associated with myopathic side effects ranging from myalgias to rhabdomyolysis and autoimmune necrotizing myositis. Statins have not been previously shown to cause myocarditis. Our case highlights this rare entity.", "affiliations": "Division of Cardiology, Department of Internal Medicine, USA.;Division of Cardiology, Department of Internal Medicine, USA.;Division of Cardiology, Department of Internal Medicine, USA.;Department of Medical Imaging, University of Arizona College of Medicine, Tucson, USA.;Division of Cardiology, Department of Internal Medicine, USA.", "authors": "Ajmal|Muhammad|M|https://orcid.org/0000-0002-2463-3035;Singh|Amitoj|A|;Kubba|Saad|S|;Hershman|Michelle|M|;Acharya|Tushar|T|https://orcid.org/0000-0001-7315-8368", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/6660362", "fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/6660362\nCase Report\nStatin-Induced Triad of Autoimmune Myocarditis, Myositis, and Transaminitis\nhttps://orcid.org/0000-0002-2463-3035\nAjmal Muhammad 1\nSingh Amitoj 1\nKubba Saad 1\nHershman Michelle 2 3\nhttps://orcid.org/0000-0001-7315-8368\nAcharya Tushar tacharya@shc.arizona.edu\n1 2 3\n1Division of Cardiology, Department of Internal Medicine, USA\n2Department of Medical Imaging, University of Arizona College of Medicine, Tucson, USA\n3Banner University Medical Center, Tucson, USA\nAcademic Editor: Takatoshi Kasai\n\n2021\n8 4 2021\n2021 666036222 12 2020\n11 3 2021\n30 3 2021\nCopyright © 2021 Muhammad Ajmal et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nDespite well-established cardiovascular benefits, statins have been associated with myopathic side effects ranging from myalgias to rhabdomyolysis and autoimmune necrotizing myositis. Statins have not been previously shown to cause myocarditis. Our case highlights this rare entity.\n==== Body\n1. History of Presentation\n\nA 70-year-old male presented to the emergency department (ED) with shortness of breath and generalized body aches associated with muscle weakness in all extremities. These symptoms dated back a few months; however, there was an acute decompensation in the past 1 week which led to the hospital visit. Shortness of breath was associated with orthopnea and chest discomfort. At the time of presentation to the ED, there was severe limitation of daily activities including inability to get out of bed, stand from a sitting position, and perform personal grooming. Presenting vitals were stable (pulse 84 beats per minute, blood pressure 134/60 mmHg). Physical examination demonstrated diffuse tenderness and objective weakness in all four extremities (3/5 strength). Reflexes were intact, and there were no focal neurological deficits. Cardiorespiratory examination demonstrated bibasilar crackles, an elevated JVP, and bilateral lower extremities pitting edema. An electrocardiogram demonstrated a normal dual-chamber function with ventricular pacing and atrial sensing.\n\n2. Past Medical History\n\nThe patient had known diffuse nonobstructive coronary artery disease (CAD) (by coronary angiography). Other comorbidities included chronic kidney disease stage III and complete heart block status postdual-chamber pacemaker (implanted 1 year ago). His medications included atorvastatin 80 mg daily (6 months), metoprolol tartrate 25 mg twice daily, aspirin 81 mg, and glipizide 5 mg daily.\n\n3. Differential Diagnosis\n\nClinically, the patient had signs and symptoms of a combined skeletal (proximal muscle weakness) and myocardial insult (acute heart failure with evidence of elevated filling pressures). While statins were suspected to at least be partially responsible for the clinical presentation, a unifying pathophysiology was sought and would require further testing. Subsequently, focused laboratory testing, imaging, and eventual pathological testing were performed as described below.\n\n4. Investigations\n\nLaboratory examination revealed rhabdomyolysis with acute kidney injury, transaminitis, and myocardial injury (elevated hs-troponin and NT-pro BNP). Rheumatologic workup yielded an abnormally elevated anti-HMGCR-Ab, which was suggestive of autoimmune necrotizing myositis with moderate significance (Table 1). Skeletal muscle biopsy (gastrocnemius) confirmed necrotizing myopathy and neurogenic atrophy.\n\nMagnetic resonance imaging (MRI) of the upper and lower extremities demonstrated diffuse muscular edema in keeping with acute myositis (Figure 1). Due to myocardial injury (elevated serum hs-cTnT and NT-pro BNP), cardiac involvement was suspected. An echocardiogram and subsequently a cardiac MRI were obtained. Echocardiography demonstrated normal biventricular size and function without regional wall motion abnormalities and no significant valvular abnormalities. Cardiac MRI confirmed normal biventricular size and overall LV function as seen on the echocardiogram. On tissue characterization, myocardial T1 was significantly elevated (Figure 1(a)) in the midanterolateral and inferolateral left ventricular walls suggesting expanded extracellular compartment due to edema/inflammation or fibrosis. T2 mapping images also demonstrated mildly increased values corresponding to these same areas in keeping with myocardial edema (Figure 1). On dynamic perfusion imaging, there was a resting perfusion defect in these areas, presumably due to perivascular edema or direct vascular injury. Late gadolinium enhancement imaging was diagnostic for myocarditis and showed enhancement in a midwall distribution involving the midantero- and inferolateral walls and in an epicardial distribution in the apical anterior wall (Figures 1(d), 2, 3). Our proposed algorithm for evaluating statin-induced myocarditis is shown in Figure 4.\n\n5. Management\n\nThe initial suspicion for statin-induced myositis and rhabdomyolysis was confirmed with an elevated HMGCR antibody, abnormal MRI of extremities, and inflammatory myocyte necrosis on skeletal muscle biopsy. Atorvastatin was discontinued, and patient was resuscitated with intravenous normal saline. Close cardiac monitoring and electrolyte replacement were undertaken given acute myocarditis. Through the initial week of his hospitalization, the patient's renal function improved but neuromuscular weakness and pain continued. Once fulminant necrosis was confirmed on biopsy, given persistent skeletal weakness, immunosuppressive therapies were instituted. These included intravenous Solu-Medrol (125 mg daily × 3 days) and intravenous immunoglobulin (IVIG) (2 mg/kg IVIG × 1 dose). Despite this regimen, the patient remained clinically and chemically symptomatic (total CK and liver enzymes remained elevated). This prompted a trial of intravenous rituximab (1 g). Due to ongoing need for IV immunosuppression and slow improvement in muscle strength, the patient had a protracted hospital course lasting 4 weeks. Once clinically stable, he was discharged to a short-term rehabilitation facility. His laboratory work at discharge showed an improvement in CK (2815 U/L), AST (182 U/L), ALT (411 U/L), and ALP (172 U/L). He did not develop arrhythmias during the hospital stay.\n\n6. Discussion\n\nDespite its multiple, well-documented beneficial effects in atherosclerotic cardiovascular disease, statin use has been associated with side effects like muscle and liver injury [1, 2]. Myalgias have been commonly reported with statins but only 1 out of 10,000 patients develops objective muscle injury with CK elevation [3]. Most of these resolve spontaneously with statin cessation. In contrast, statin-induced autoimmune necrotizing myositis (ANM) is very rare but potentially life-threatening. It is diagnosed with antibodies to HMGCR and muscle necrosis on biopsy. ANM requires aggressive immunosuppression in addition to statin cessation [4–6].\n\nStatin-induced myocarditis with or without associated autoimmune necrotizing myositis has not been reported in literature before. In fact, some reports suggest that statins may be helpful in treating myocarditis and postmyocarditis dilated cardiomyopathy [7]. This beneficial effect in myocarditis and particularly autoimmune myocarditis is thought to be due to anti-inflammatory/pleotropic effects of statins and possibly mediated by inhibition of antigen-presenting cells and lymphocytes leading to quiescence of an inflammatory surge and reduction in inflammatory biomarkers [8].\n\nContrary to these reports, our case represents a rare instance where statins can act as an offender and result in autoimmune myocarditis. Myocarditis is likely mediated by direct tissue injury not too different in its pathogenesis from the necrotizing myositis of the skeletal muscle. It is hypothesized that statin-induced overexpression of HMGCAR in genetically susceptible individuals may lead to autoimmunity against HMGCAR causing muscle injury. Since injured muscles produce more HMGCAR, this may perpetuate a cycle that may not be abated by discontinuation of statin and require immunosuppression [5].\n\nReaders should familiarize themselves with this extremely rare adverse effect, especially in setting of elevated cardiac enzymes, which can be misinterpreted as acute coronary syndrome instead of myocarditis.\n\n7. Follow-Up\n\nThe patient was an outpatient in the cardiology and rheumatology clinic 4-week posthospital discharge and continued to show clinical improvement (he could now walk without support). His steroid regimen is gradually being tapered over 6 months with close rheumatologic follow-up.\n\n8. Conclusion\n\nThis is the first reported case of statin-induced myocarditis. Myocarditis in this patient is likely a part of the larger spectrum of statin-induced autoimmune necrotizing myositis, a very rare condition managed with aggressive immunosuppressants.\n\n9. Learning Objectives\n\nRecognize autoimmune necrotizing myositis and myocarditis as a rare complication of statin use\n\nDiagnosis and management of this life-threatening myopathy\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a) Bright signal intensity on T1 map showing increased extracellular compartment due to inflammation/fibrosis. (b) Bright signal intensity on T2 map corresponding to inflammation/edema. (c) Normal (yellow arrow) and abnormal (red arrow) perfusion due to vascular injury/myocardial edema in the areas corresponding to (d) late gadolinium enhancement (LGE).\n\nFigure 2 Late gadolinium enhancement (red arrows) in a midwall and epicardial distribution involving the inferolateral, anterolateral, and anterior walls consistent with myocarditis (short axis stack).\n\nFigure 3 Late gadolinium enhancement (red arrows) in a midwall and epicardial distribution involving the inferolateral, anterolateral, and anterior walls consistent with myocarditis (long axes).\n\nFigure 4 Algorithm for evaluating statin-induced myocarditis (LGE (late gadolinium enhancement)).\n\nTable 1 Laboratory findings.\n\nLaboratory\tPatient's results\tNormal value\t\nWhite blood cells\t7.3 K/mm3\t4-11 K/mm3\t\nHemoglobin\t10.7 g/dL\t13.5-17 g/dL\t\nPlatelets\t230 K/mm3\t130-450 K/mm3\t\nSodium\t141 mmol/L\t134-147 mmol/L\t\nPotassium\t5.3 mmol/L\t5.3 mmol/L\t\nChloride\t110 mmol/L\t95-108 mmol/L\t\nBicarbonate\t17 mmol/L\t>19 mmol/L\t\nBUN\t67 mg/dL\t8-25 mg/dL\t\nCreatinine\t1.8 mg/dL\t<1.5 mg/dL\t\nAnion gap\t14\t\t\nAST\t716 U/L\t<50 U/L\t\nALT\t907 U/L\t<60 U/L\t\nALP\t389 U/L\t<140 U/L\t\nhs-troponin\t1577 ng/L − >1619 ng/L − >1538 ng/L\t<11 ng/L\t\nNT-pro BNP\t2427 pg/mL\t<124 pg/mL\t\nCK\t29,200 U/L\t<355 U/L\t\nCK-MB\t525 ng/ml\t<6.7 ng/mL\t\nSerum aldolase\t130 IU/L\t<7.6 IU/L\t\nESR\t85\t<30\t\nHMGCR-Ab\t59\t<20\t\nANA\tNegative\tNegative\t\nASMA\tNegative\tNegative\t\nAnti-Jo1 antibodies\tNegative\tNegative\t\nAST: aspartate aminotransferase; ALT: alanine transaminase; ALP: alkaline phosphatase; NT-pro BNP: N-terminal probrain natriuretic peptide; CK: total creatine kinase; CK-MB: creatine kinase-myocardial band; ESR: erythrocyte sedimentation rate; HMGCR-Ab: β-hydroxy β-methylglutaryl-CoA reductase antibody; ANA: antinuclear antibodies; ASMA: antismooth muscle antibodies.\n==== Refs\n1 Grundy S. Stone M. Bailey A. L. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines Circulation 2019 139 25 e1082 e1143 10.1161/CIR.0000000000000625 2-s2.0-85068374636 30586774\n2 Lee W.-S. Kim J. Statin-induced liver and muscle toxicities Molecular & Cellular Toxicology 2019 15 1 9 17 10.1007/s13273-019-0002-3 2-s2.0-85059158989\n3 Law M. Rudnicka A. R. Statin safety: a systematic review The American Journal of Cardiology 2006 97 8A 52C 60C 10.1016/j.amjcard.2005.12.010 2-s2.0-33645881669 16581329\n4 Nazir S. Lohani S. Tachamo N. Poudel D. Donato A. Statin-associated autoimmune myopathy: a systematic review of 100 cases Journal of Clinical Rheumatology 2017 23 3 149 154 10.1097/RHU.0000000000000497 2-s2.0-85014598543 28277343\n5 Mammen A. L. Statin-associated autoimmune myopathy The New England Journal of Medicine 2016 374 7 664 669 10.1056/NEJMra1515161 2-s2.0-84959036898 26886523\n6 Sharma P. Timilsina B. Adhikari J. Parajuli P. Dhital R. Tachamo N. Statin-induced necrotizing autoimmune myopathy: an extremely rare adverse effect from statin use J Community Hosp Intern Med Perspect 2019 9 6 503 506 10.1080/20009666.2019.1702272 32002159\n7 Lazzerini P. E. Capecchi P. L. Laghi-Pasini F. Statins as a new therapeutic perspective in myocarditis and postmyocarditis dilated cardiomyopathy Cardiovascular Drugs and Therapy 2013 27 5 365 369 10.1007/s10557-013-6475-8 2-s2.0-84885186836 23832693\n8 Wu J. L. Matsui S. Zong Z. P. Amelioration of myocarditis by statin through inhibiting cross-talk between antigen presenting cells and lymphocytes in rats Journal of Molecular and Cellular Cardiology 2008 44 6 1023 1031 10.1016/j.yjmcc.2008.03.016 2-s2.0-44649111169 18471827\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2021()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "6660362", "pmc": null, "pmid": "33898067", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "23832693;32002159;28277343;26886523;16581329;18471827;30586774", "title": "Statin-Induced Triad of Autoimmune Myocarditis, Myositis, and Transaminitis.", "title_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis" }

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STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REP CARDIOL. 2021?UNKNOWN:UNKNOWN?UNKNOWN. DOI:10.1155/2021/6660362", "literaturereference_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210525", "receivedate": "20210525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19299847, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-APOTEX-2021AP011537", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": 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"AJMAL M, SINGH A, KUBBA S, HERSHMAN M AND ACHARYA T.. 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STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. 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STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REPORTS IN CARDIOLOGY. 2021?ARTICLE NUMBER 6660362:2021. 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIPIZIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Necrotising myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Autoimmune myositis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiac failure acute", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Left ventricular end-diastolic pressure increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Autoimmune myocarditis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AJMAL M, SINGH A, KUBBA S, HERSHMAN M, ACHARYA T. STATIN?INDUCED TRIAD OF AUTOIMMUNE MYOCARDITIS, MYOSITIS, AND TRANSAMINITIS. CASE REPORTS IN CARDIOLOGY. 2021?.", "literaturereference_normalized": "statin induced triad of autoimmune myocarditis myositis and transaminitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210521", "receivedate": "20210521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19287005, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Acute generalized exanthamous pustulosis (AGEP)is a rare eruption of non-follicular sterile pustuleson a diffuse background of erythema and edema,commonly associated with fever and leukocytosis.Antibiotics are implicated in most cases; however,other drugs have been reported to cause AGEP. Wereport a case of a 73-year-old man with a historyof ulcerative colitis who presented with a diffusepustular rash, renal failure, elevated liver functiontests, and leukocytosis with neutrophilia. A week priorto admission, the patient was started on mesalamineto treat colitis. Upon admission, a workup includinga skin biopsy was performed and was consistentwith AGEP. Mesalamine was discontinued, and thepatient's skin eruption, renal function, liver functiontests, and leukocytosis subsequently improved.Mesalamine has an unknown mechanism of action.However, it is thought to be an anti-inflammatoryagent that blocks the production of leukotrienesand prostaglandins and is an immunosuppressantthat increases the release of adenosine, whichinterferes with leukocyte function. The decrease inprostaglandin synthesis or deregulation of leukocytefunction caused by mesalamine may be the etiologyin this case. Discontinuation of the offending agentleads to resolution of AGEP, as it did in this patient.", "affiliations": "Skin Institute of South Florida, Coral Springs, Florida. kyunghwamd@ gmail.com.", "authors": "Rocci|Erin|E|;Park|Kelly|K|;Hutchens|Kelli|K|;Winterfield|Laura|L|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2108", "issue": "23(1)", "journal": "Dermatology online journal", "keywords": null, "medline_ta": "Dermatol Online J", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D006801:Humans; D008297:Male; D019804:Mesalamine", "nlm_unique_id": "9610776", "other_id": null, "pages": null, "pmc": null, "pmid": "28329471", "pubdate": "2017-01-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "First report of mesalamine (5-aminosalicylic acid) as the causative agent in a case of acute generalized exanthamous pustulosis.", "title_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis" }

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FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. DERMATOLOGY ONLINE JOURNAL. 2016;23(1):7", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170309", "receivedate": "20170309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13312984, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-MEDA-2016060114", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.8 GRAMS PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.8", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "054", "drugauthorizationnumb": "019618", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUPPOSITORY", "drugdosagetext": "4 GRAMS PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute generalised exanthematous pustulosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ROCCI E,PARK, MD, MS K,HUTCHENS, MD K,WINTERFIELD, MD, MPH L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2016; 74(1): 1-4{BR}ROCCI, BS E,PARK, MD, MSL K,HUTCHENS, MD K,WINTERFIELD, MD, MPH L. FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. 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FIRST REPORT OF MESALAMINE (5?AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. 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FIRST REPORT OF MESALAMINE (5-AMINOSALICYLIC ACID) AS THE CAUSATIVE AGENT IN A CASE OF ACUTE GENERALIZED EXANTHAMOUS PUSTULOSIS. DERMATOLOGY ONLINE JOURNAL 23: NO. 1 JANUARY 2017", "literaturereference_normalized": "first report of mesalamine 5 aminosalicylic acid as the causative agent in a case of acute generalized exanthamous pustulosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170314", "receivedate": "20160624", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12497351, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "Tuberculosis (TB) is still considered a major global public health problem in the world and there is a concern about the worldwide increase of drug-resistance (DR). This paper describes the analysis of three Mycobacterium tuberculosis isolates from a single patient collected over a long treatment period of time. DR was initially investigated through phenotypic testing, followed by line probe assays (LPAs) and whole genome sequencing (WGS). It presents an intriguing situation where a multidrug-resistant (MDR-) TB case was diagnosed and treated based only on late phenotypic drug susceptibility testing of isolate 1. During the treatment, another two isolates were cultivated: isolate 2, nine months after starting MDR-TB treatment; and isolate 3, cultivated five months later, during regular use of anti-TB drugs. These two isolates were evaluated using molecular LPA and WGS, retrospectively. All mutations detected by LPA were also detected in the WGS, including conversion from fluoroquinolones susceptibility to resistance from isolate 2 to isolate 3. WGS showed additional mutations, including some which may confer resistance to other drugs not tested (terizidone/cycloserine) and mutations with no correspondent resistance in drug susceptibility testing (streptomycin and second-line injectable drugs).", "affiliations": "Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.;Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.;Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil. Electronic address: vbollela@gmail.com.", "authors": "Silva Feliciano|Cinara|C|;Rodrigues Plaça|Jessica|J|;Peronni|Kamila|K|;Araújo Silva|Wilson|W|;Roberto Bollela|Valdes|V|", "chemical_list": "D000995:Antitubercular Agents; D001426:Bacterial Proteins", "country": "Brazil", "delete": false, "doi": null, "fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(16)30036-8\n10.1016/j.bjid.2016.01.004\nBrief Communication\nEvaluation of resistance acquisition during tuberculosis treatment using whole genome sequencing\nSilva Feliciano Cinara a\nRodrigues Plaça Jessica c\nPeronni Kamila bc\nAraújo Silva Wilson Jr bc\nRoberto Bollela Valdes vbollela@gmail.com\nac⁎\na Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil\nb Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil\nc Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil\n⁎ Corresponding author. vbollela@gmail.com\n20 3 2016\nMay-Jun 2016\n20 3 2016\n20 3 290293\n28 10 2015\n5 1 2016\n© 2016 Elsevier Editora Ltda.\n2016\nElsevier Editora Ltda.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nTuberculosis (TB) is still considered a major global public health problem in the world and there is a concern about the worldwide increase of drug-resistance (DR). This paper describes the analysis of three Mycobacterium tuberculosis isolates from a single patient collected over a long treatment period of time. DR was initially investigated through phenotypic testing, followed by line probe assays (LPAs) and whole genome sequencing (WGS). It presents an intriguing situation where a multidrug-resistant (MDR-) TB case was diagnosed and treated based only on late phenotypic drug susceptibility testing of isolate 1. During the treatment, another two isolates were cultivated: isolate 2, nine months after starting MDR-TB treatment; and isolate 3, cultivated five months later, during regular use of anti-TB drugs. These two isolates were evaluated using molecular LPA and WGS, retrospectively. All mutations detected by LPA were also detected in the WGS, including conversion from fluoroquinolones susceptibility to resistance from isolate 2 to isolate 3. WGS showed additional mutations, including some which may confer resistance to other drugs not tested (terizidone/cycloserine) and mutations with no correspondent resistance in drug susceptibility testing (streptomycin and second-line injectable drugs).\n\nKeywords\n\nTuberculosis\nDrug resistant tuberculosis\nDrug susceptibility tests\nWhole genome sequencing\n==== Body\npmcTuberculosis (TB) is still considered a major global public health problem, and Brazil is the 16th country in absolute number of cases. Despite consistent advances achieved with control measures, there are still major challenges to face the growing resistance to anti-tuberculosis drugs in several countries, including Brazil.1 Molecular epidemiology studies of M. tuberculosis have gained emphasis among clinical researchers. New knowledge on the TB pathogenesis and its causative agent could be the key to the development of new control strategies.2, 3 Recently, the World Health Organization set the Global “Stop TB Plan” to find patients harboring resistant strains of M. tuberculosis. This initiative has been important to test first-line TB drugs and promoting research to develop new drugs, vaccines, and diagnostic strategies.1, 4\n\nAmong the techniques used, whole genomic sequencing (WGS) is worth mentioning, especially for the investigation of bacilli resistance. This approach enables accurate assessment of mutations related to bacilli resistance to several TB drugs. This information would allow the development of new diagnostic methods and therapeutic strategies applied for disease control.5\n\nOuthred et al. advocate the use of WGS for all multidrug-resistant M. tuberculosis isolates as an alternative plan to improve patient care, monitor for transmission events, and contribute to better understanding of resistance-associated mutations.6\n\nThis study describes a challenging case of treatment failure of a patient under MDR-TB therapy and reports phenotypic and molecular drug resistance test results in correlation to mutations identified with a whole genome sequencing analysis.\n\nThree isolates of M. tuberculosis from a single patient, during different time points of his treatment, were evaluated based on phenotyping and genotyping testing: isolate 1 was collected before the patient started the follow-up in the reference center, when clinical and microbiological failure was diagnosed, despite regular TB treatment with rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E); isolate 2 was collected in the ninth month of MDR-TB treatment (other clinical and microbiological failure); and isolate 3 was obtained on the 13th month of MDR-TB treatment.\n\nA nonradiometric phenotypic susceptibility testing was performed in liquid medium (MGIT 960; Becton Dickinson Diagnostic Systems, Sparks, MD) for isolate 1. Besides this susceptibility phenotypic testing, two line probe assays (LPA), Genotype MTBDRplus and MTBDRsl (Hain Lifescience, GmbH, Germany), were performed in isolates 2 and 3. Genotype MTBDRplus evaluates the main mutations associated with rifampicin (rpoB gene mutations) and isoniazid (katG e inhA mutations) resistance. Genotype MTBDRsl detects mutations related with resistance to fluoroquinolones (gyrA gene mutations), second-line injectable drugs (SLID) (rrs gene mutations) and ethambutol (embB gene mutations).7, 8 Finally, the two stored samples (isolates 2 and 3) were submitted to WGS analysis using Illumina MiSeq Sequecing System (Illumina, San Diego, CA, USA). LPAs and WGS tests were performed with stored isolates 2 and 3 at the end of the patient's treatment. Therefore, this information was not available to the clinician during the treatment. Isolate 1 was not tested again because it was not viable.\n\nGenerated reads with phred scale score superior to 30 was mapped with BWA v0.7.5a program (Burrows-Wheeler Alignment Tool) using the reference genome M. tuberculosis H37Rv. Conversion from sequence alignment map format to sorted, indexed BAM files was done using SAMtools (version 0.1.19). PCR-duplicates were removed using the MarkDuplicates option of the Picard software tools (version 1.61). The variants were found according to the pipeline SAMtools/BCFtools v 0.1.18 and annotated with SnpEff v 4.0. Databases TB Drug Resistance Mutation Database9 and M. tb Drug Resistance Directed Sequencing Database10 were used to identify mutations described for the TB bacilli. All detected mutations were confirmed based on TB profiler online tool, described by Coll et al.,11 to remove single nucleotide polymorphisms (SNPs) at drug resistance loci which were historically misclassified as drug resistance markers.\n\nThis project was approved by the Ethics and Research Committee of the Hospital of the Ribeirão Preto Medical School of the University of São Paulo (protocol number: 944117 – February 1, 2015).\n\nThe patient was initially treated with RHZE for six months. During the last month clinical and microbiological failure (acid-fast smear positive and respiratory symptoms) was diagnosed. This M. tuberculosis isolate showed R and H resistance in the first phenotypic susceptibility testing. The patient was referred to the regional TB drug resistance center and his treatment was switched to streptomycin (Sm), E, ofloxacin (FQ), Z, and terizidone (Tz), following the Brazilian guidelines for the management of MDR-TB. During the first nine months of treatment, there was a transient improvement followed by recurrence of symptoms. Sputum culture was collected and the same MDR-TB treatment was maintained until the 13th month. The therapy was empirically optimized by adding ethionamide, extending the period of streptomycin and increasing the local support for directly observed treatment, while the results of phenotypic testing from isolate 3 were still pending. The treatment was successfully completed after 24 months, with clinical and microbiological cure. After that, instigated by this unusual and intriguing case and its outcome, we decided to carry on molecular studies on the patient's isolates 2 and 3.\n\nIsolate 1 showed resistance to R and H in the phenotypic test. Phenotypic testing of isolate 2 showed resistance to these two drugs and also to Z. The LPA of this isolate showed resistance to R (lost wild type 8 and gained rpoB S450L mutation), H (lost wild type and gained KatG S315T1 mutation), and E (lost wild type 1 and gained embB M306V mutation). Isolate 3 showed resistance to R, I, E (same mutations described in isolate 2), and acquired a new resistance pattern to FQ (gyrA D94G mutation) in the LPA test. Phenotypic testing of isolate 3, which became available close to the end of the patient's treatment, showed resistance to the above mentioned drugs and also to Z. The critical concentrations of Bactec-MGIT 960™ reported by the manufacturer's drug susceptibility testing (DST) protocol were as follows: H: 0.10 μg/mL; R: 1.0 μg/mL; EM: 5.0 μg/mL; Sm: 1.0 μg/mL; Z: 100 μg/mL; FQ (ofloxacin): 2 μg/mL; Amikacin 1.0 μg/mL; Capreomycin 2.5 μg/mL. The susceptibility profile of isolates in the phenotypic test and LPA are described in Table 1.Table 1 Results of phenotypic and LPA tests: susceptibility profile of tested drugs.\n\nTable 1\tIsolate 1 detected resistance\tIsolate 2 detected resistance\tIsolate 3 detected resistance\t\nPhenotypic drug susceptibility testing (DST)\tRifampicin; Isoniazida\tRifampicin; Isoniazid;\tRifampicin; Isoniazid\t\n\t\tPyrazinamideb\tOfloxacin; Pyrazinamide\t\n\t\t\tEthambutolc\t\n\n\n\t\nGenotype MTBDRplus (R; H)\tNA\tRifampicin\tRifampicin\t\n\t\tIsoniazid\tIsoniazid\t\n\n\n\t\nGenotype MTBDRsl (E; FQ; SLID)\tNA\tEthambutol\tEthambutol\t\n\t\t\tFQ\t\n\n\n\t\nWGS\tNA\tAvailable (see Table 2)\tAvailable (see Table 2)\t\nNA, not available; R, rifampicin; H, isoniazid; E, ethambutol; FQ, fluoroquinolones; SLID, second line injectable drugs.\n\na Isolate 1 collected before MDR-TB treatment – susceptible to E and Sm. SLID not tested.\n\nb Isolate 2 collected in the ninth month of MDR-TB treatment – susceptible to E, SLID and FQ.\n\nc Isolate 3 collected on the 13th month of MDR-TB treatment – susceptible to Sm and SLID.\n\nThe WGS analysis of these two strains generated the total of 43,036,497 reads (28,171,267 for strain 1 and 14,865,230 for strain 2), with an average coverage of 469× for the isolate 2 and 244× for the isolate 3. Bioinformatics analysis reported 11 mutations already described as associated with resistance in isolate 2 and 12 mutations in isolate 3 (Table 2). Additional mutation in gyrA gene (D94G) was identified in isolate 3, which is one of the most frequent mutations associated with resistance to FQ, and is tested by the LPA Genotype MTBDRsl. Although all mutations showed by LPA were validated by WGS, additional mutations were detected, including those conferring resistance to other drugs despite bacilli susceptibility demonstrated in the phenotypic drug susceptibility testing (gyrA E21Q in isolate 2, rpsL promoter gene in genomic position 781395, tlyA L11L for isolates 2 and 3).Table 2 Whole genomic sequencing mutations identified in isolates 2 and 3.\n\nTable 2Gene\tAssociated drug\tGenomic position\tMutation\tStrain 2 mutation\tStrain 3 mutation\tReference allele\tMutated allele\tVariant type\t\ngyrA\tFluoroquinolones\t7362\tE21Q\tYes\tYes\tG\tC\tMissense\t\ngyrA\tFluoroquinolones\t7582\tD94Ga\tNo\tYes\tA\tG\tMissense\t\nrpoB\tRifampicin\t759939\tP45T\tYes\tYes\tC\tA\tMissense\t\nrpoB\tRifampicin\t761155\tS450L\tYes\tYes\tC\tT\tMissense\t\nrpsL\tStreptomycin\t781395\t–\tYes\tYes\tT\tC\tPromoter gene\t\ntlyA\tAminoglycosides\t1917972\tL11L\tYes\tYes\tA\tG\tSynonymous\t\nkatG\tIsoniazid\t2154915\tE399E\tYes\tYes\tA\tG\tSynonymous\t\nkatG\tIsoniazid\t2155168\tS315T\tYes\tYes\tG\tC\tMissense\t\npncA\tPyrazinamide\t2289039\tW68L\tYes\tYes\tG\tT\tMissense\t\nalr\tCycloserine\t3840719\tL234L\tYes\tYes\tA\tG\tSynonymous\t\nalr\tCycloserine\t3841403\tE6D\tYes\tYes\tG\tT\tMissense\t\nembB\tEthambutol\t4247429\tM306V\tYes\tYes\tA\tG\tMissense\t\na Mutation detected only in the isolate 3, by whole genomic sequencing.\n\nExcept for mutation D94G, the SNPs reads for isolate 2 and 3 were 100% identical, with no signs of heteroresistance.\n\nThe relation between genome mutations and phenotypic resistance is particularly important for therapeutic decision, because different mutations can cause different resistance profiles or not even cause any phenotypic resistance.12 Coll et al. compiled a library of mutations predictive of drug resistance, and removed phylogenetic SNPs at drug resistance loci, which were historically misclassified as drug resistance markers.11\n\nWGS has great application potential to detect bacilli resistance in clinical practice. However, further work is needed to determine additional resistance polymorphisms as it should be noted that high positive predictive values are crucial for drug resistance tests where the consequence of a false positive result may lead to unnecessary treatment and prolonged patient isolation.11\n\nThe WGS of M. tuberculosis is a great advance in the knowledge of bacilli resistance, as well as in the clinical management of TB. This technique presents greater discriminatory power, enabling analysis of additional mutations, not possible to be assessed by other methods. WGS has the potential for clinical use, as mentioned by other authors6, 11, 12, 13, 14 for fast and accurate assessments in cases of illness caused by strains resistant to multiple drugs, with an impact on therapeutic decisions. However, this is a high-cost technology and it is still critical to understand and standardize correlations between genotypic and phenotypic resistance to really optimize its clinical use.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 World Health Organization (WHO) Global tuberculosis report 2014 2014 World Health Organization Geneva\n2 Gomes H.M. Elias A.R. Oelemann M.A.C. Spoligotypes of Mycobacterium tuberculosis complex isolates from patients residents of 11 states of Brazil Infect Genet Evol 12 4 2012 649 656 10.1016/j.meegid.2011.08.027 Epub 2011 Sep 1 21907830\n3 García De Viedma D. Mokrousov I. Rastogi N. Innovations in the molecular epidemiology of tuberculosis Enferm Infecc Microbiol Clin 29 Suppl 1 2011 8 13 10.1016/S0213-005X(11)70012-X\n4 World Health Organization (WHO) The global plan to stop TB 2011–2015 2010 World Health Organization Geneva\n5 Ilina E.N. Shitikov E.A. Ikryannikova L.N. Comparative genomic analysis of Mycobacterium tuberculosis drug resistant strains from Russia PLoS One 8 2013 e56577 23437175\n6 Outhred A.C. Jefs P. Suliman B. Added value of whole genome sequencing for management of highly drug-resistant TB J Antimicrob Chemother 70 4 2015 1198 1202 25492392\n7 World Health Organization (WHO) Molecular line probe assays for rapid screening of patients at risk of multi-drug resistant tuberculosis (MDR-TB) 2008 World Health Organization Geneva\n8 Brossier F. Veziris N. Aubry A. Detection by genotype MTBDRsl test of complex mechanisms of resistance to second-line drugs and ethambutol in multidrug-resistant Mycobacterium tuberculosis complex isolates J Clin Microbiol 48 2010 1683 1689 20335420\n9 Sandgren A. Strong M. Muthukrishnan P. Tuberculosis drug resistance mutation database PLoS Med 6 2009 e2 19209951\n10 Broad Institute. Available at: http://www.broadinstitute.org/annotation/genome/mtb_drug_resistance.1/MultiHome.htm.\n11 Coll F. McNerney R. Preston M.D. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences Genome Med 7 2015 51 26019726\n12 Witney A.A. Gould K.A. Arnold A. Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases J Clin Microbiol 53 2015 1473 1483 25673793\n13 Liu F. Hu Y. Wang Q. Comparative genomic analysis of Mycobacterium tuberculosis clinical isolates BMC Genomics 15 2014 469 24923884\n14 Clark T.G. Mallard K. Cell F. Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing PLoS One 8 2013 e83012 24349420\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1413-8670", "issue": "20(3)", "journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases", "keywords": "Drug resistant tuberculosis; Drug susceptibility tests; Tuberculosis; Whole genome sequencing", "medline_ta": "Braz J Infect Dis", "mesh_terms": "D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004351:Drug Resistance; D054908:Extensively Drug-Resistant Tuberculosis; D006801:Humans; D009169:Mycobacterium tuberculosis; D013997:Time Factors", "nlm_unique_id": "9812937", "other_id": null, "pages": "290-3", "pmc": null, "pmid": "27004922", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": null, "title": "Evaluation of resistance acquisition during tuberculosis treatment using whole genome sequencing.", "title_normalized": "evaluation of resistance acquisition during tuberculosis treatment using whole genome sequencing" }

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{ "abstract": "BACKGROUND\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4% of all ectopic pregnancies. It also represents one of the few times an ectopic pregnancy can be carried to term. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk. After an extensive search of the English language medical literature, we are unaware of any case of abdominal pregnancy in which the placenta was receiving its vascular supply from the sacral plexus.\n\n\nMETHODS\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days' gestation, presented to our Emergency Department with abdominal pain. She did not complain of any vaginal bleeding. A physical examination revealed mild abdominal tenderness and no blood in the vaginal vault. Laboratory findings corresponded to an increased level of beta human chorionic gonadotropin; magnetic resonance imaging confirmed an abdominal pregnancy. She underwent feticide, administration of methotrexate and a laparotomy was done which was immediately deferred due to perceived increased bleeding risk. She was found to have an intra-abdominal ectopic pregnancy with the placenta attached to her omentum, cul-de-sac and rectosigmoid, with unusual and extensive vascularity from the sacral plexus. A repeat laparotomy was performed 11 weeks later, aimed at removal of the gestational sac and placenta that were left in situ on the first laparotomy. This time, we achieved successful removal of the peritoneal gestation, lysis of adhesions, ligation of vascular supply and cautery of the diminished vasculature. Subsequently, she had two ectopic pregnancies, which were managed with both medical and surgical interventions.\n\n\nCONCLUSIONS\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10% of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in future pregnancies. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility; however, surgery remains an acceptable modality. We found that careful and strategic choice of management pathway can make all the difference to a favorable outcome. As emergency physicians, we need to be aware of the possibility of abdominal ectopic pregnancy in such presentations and its severe consequences if it remains undiagnosed.", "affiliations": "Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. drpatelchaitali@gmail.com.;Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. jfeldman@hackensackUMC.org.;Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ, 07601, USA. cogedegbe@hackensackUMC.org.", "authors": "Patel|Chaitali|C|;Feldman|Joseph|J|;Ogedegbe|Chinwe|C|", "chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate", "country": "England", "delete": false, "doi": "10.1186/s13256-016-0808-8", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 80810.1186/s13256-016-0808-8Case ReportComplicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4-year follow-up: a case report Patel Chaitali drpatelchaitali@gmail.com Feldman Joseph jfeldman@hackensackUMC.org Ogedegbe Chinwe cogedegbe@hackensackUMC.org Hackensack University Medical Center, 30, Prospect Ave, Hackensack, NJ 07601 USA 11 2 2016 11 2 2016 2016 10 3725 9 2015 10 1 2016 © Patel et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4 % of all ectopic pregnancies. It also represents one of the few times an ectopic pregnancy can be carried to term. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk. After an extensive search of the English language medical literature, we are unaware of any case of abdominal pregnancy in which the placenta was receiving its vascular supply from the sacral plexus.\n\nCase presentation\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days’ gestation, presented to our Emergency Department with abdominal pain. She did not complain of any vaginal bleeding. A physical examination revealed mild abdominal tenderness and no blood in the vaginal vault. Laboratory findings corresponded to an increased level of beta human chorionic gonadotropin; magnetic resonance imaging confirmed an abdominal pregnancy. She underwent feticide, administration of methotrexate and a laparotomy was done which was immediately deferred due to perceived increased bleeding risk. She was found to have an intra-abdominal ectopic pregnancy with the placenta attached to her omentum, cul-de-sac and rectosigmoid, with unusual and extensive vascularity from the sacral plexus. A repeat laparotomy was performed 11 weeks later, aimed at removal of the gestational sac and placenta that were left in situ on the first laparotomy. This time, we achieved successful removal of the peritoneal gestation, lysis of adhesions, ligation of vascular supply and cautery of the diminished vasculature. Subsequently, she had two ectopic pregnancies, which were managed with both medical and surgical interventions.\n\nConclusions\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10 % of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in future pregnancies. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility; however, surgery remains an acceptable modality. We found that careful and strategic choice of management pathway can make all the difference to a favorable outcome.\n\nAs emergency physicians, we need to be aware of the possibility of abdominal ectopic pregnancy in such presentations and its severe consequences if it remains undiagnosed.\n\nKeywords\nAbdominal pregnancyEctopicLaparoscopyLaparotomyPeritonealPlacentaRecurrent ectopic pregnancySacral plexusSalpingotomyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nEctopic pregnancy occurs when the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. Abdominal pregnancies are rare types of ectopic pregnancies with high rates of maternal morbidity and mortality when encountered anywhere in the world [1]. Abdominal pregnancy accounts for up to 1.4 % of ectopic pregnancies [2]. The prevalence of ectopic pregnancy among women who go to an emergency department with first trimester bleeding, pain, or both ranges from 6 to 16 % [3]. These pregnancies can go undetected until an advanced fetal age and often result in severe hemorrhage [4]. Rates of maternal mortality for ectopic pregnancy in the United States have been reported as high as 20 % [5, 6]. The most common extrauterine location is the fallopian tube, accounting for 98 % of all ectopic gestations, but other possible sites include: cervical, interstitial (also referred to as cornual), hysterotomy scar, intramural, ovarian, or abdominal. Risk factors for ectopic pregnancy should be sought, including prior ectopic pregnancy, current use of an intrauterine device, prior tubal ligation, and in vitro fertilization (IVF). The risk of ectopic pregnancy increases with advancing maternal age, age over 35 years being a significant risk factor [1], and one third of the cases are thought to be associated with cigarette smoking [7]. The clinical presentation is variable, and the optimal approach to the evaluation and management of abdominal pregnancy is not well determined [8, 9]. Diagnosis can be made with a transvaginal ultrasound scan (TVS) which can identify an intrauterine pregnancy (IUP) or ectopic pregnancy [10]. In cases where an abdominal ectopic pregnancy is suspected and ultrasound is inconclusive, a diagnostic laparoscopy may be required [11]. Management of these pregnancies has changed dramatically over the years [12]. Medical and surgical interventions to these rare pregnancies are considered based on their presentation. Methotrexate treatment may be administered on a case-by-case basis, but surgical involvement may be imperative for some patients with abdominal pregnancies, particularly those presenting with rupture and who are in a state of hypovolemic shock and compromise. The 1997 to 1999 and 2003 to 2005 Confidential Enquiries into Maternal Deaths in the United Kingdom reports highlighted that most of the women who died from ectopic pregnancy were misdiagnosed in the primary care or accident and emergency settings [13, 14].\n\nWe present an unusual case that highlights the difficult clinical course of an abdominal ectopic pregnancy managed via strategic procedural intervention, as well as two separate presentations of recurrent ectopic pregnancies over a 4-year follow-up period in the same patient.\n\nCase presentation\nA 26-year-old African-American woman, primigravida, at 16 weeks 4 days’ gestation, presented to our ED with increasing abdominal pain and a positive home pregnancy test. She admitted that she had not been receiving prenatal care. She also asked for a termination of this pregnancy, if we confirmed that it was “abnormal”.\n\nShe described 3 out of 10 (mild) bilateral abdominal pain but denied any vaginal bleeding, nausea, vomiting, headache, fever, chills, dysuria or hematuria. She reported 1 to 2 weeks of severe constipation, but denied any melena or hematochezia. She also denied any history of abnormal pap smears, sexually transmitted diseases, or abnormal menses. At the time of her ED presentation she was not on any medications. She had a one pack week cigarette smoking history but denied any alcohol or other drug use. She reported being sexually active with one partner. She further mentioned that she was at a nearby hospital where pregnancy was confirmed and further testing had been done from where she signed out against medical advice (AMA).\n\nHer vital signs were: blood pressure (BP) 125/67 mmHg, pulse 115/minute, temperature 98.7 °F (37.1 °C), respiratory rate 16/minute, body mass index (BMI) 17.75 kg/m2, and oxygen saturation (SPO2) 99 %.\n\nHer physical examination was only significant for a soft non-distended abdomen, with mild diffuse lower abdominal tenderness maximal in the left lower quadrant of her abdomen. A pelvic examination, including a speculum examination, documented a normal appearing cervix, no active bleeding, and non-tender adnexa; a bimanual examination confirmed her cervix was closed and her uterus was enlarged, approximately 8 weeks in size. In our ED, she was seen by Obstetrics/Gynecology consult service. Diagnostics included initial and interval laboratory testing, as well as imaging studies, which included an ultrasound of the abdomen (transvaginal and transabdominal), magnetic resonance imaging (MRI) and a computed axial tomography (CAT) scan, (see Fig 1) of her abdomen. The results were as follows:Initial laboratory results were hemoglobin (Hb) 9.8 (anemia), hematocrit (HCT) 27.2, platelets 148, white blood cell count (WBC) 7.4, blood urea nitrogen (BUN) 4, creatinine 0.5, electrolytes were within normal ranges, albumin 2.9, partial thromboplastin time (PTT) 33, international normalized ratio (INR) 1.1, prothrombin time (PT) 13.5, beta human chorionic gonadotropin (BHCG) 134,494, fibrinogen 439, human immunodeficiency virus (HIV)-negative and RH positive.\n\nMRI: intra-abdominal ectopic pregnancy with the placenta connected to the sacral plexus. Ultrasound of the abdomen (transvaginal and transabdominal), (see Fig 2) as well as abdominal CAT scans with and without contrast showed uterus measuring 9.0×5.8×8.2 cm; no IUP; live intra-abdominal pregnancy was present within her pelvis, ventral to the uterus and measuring 7.2×12 cm.Fig. 1 Computed tomography angiogram of abdomen and pelvis. 1 Intra-abdominal pregnancy. 2 Hematoma in cul-de-sac. 3 Uterus\n\nFig. 2 Ultrasound of abdomen and pelvis. 1 Gestational sac. 2 Fetus (extrauterine pregnancy – right adnexa)\n\n\n\n\n\nShe was counselled on termination of the pregnancy due to the gravity of the medical and surgical comorbidities, and she underwent feticide via ultrasound-guided fetal intracardiac potassium chloride injection on the second day after presentation, gestational age corresponding to 16 weeks and 6 days. She received four alternate doses of methotrexate on the third, fifth and seventh day from presentation with interval leucovorin rescue on alternate days and then had an infraumbilical laparotomy for pelvic exploration and planned fetus removal. A laparotomy was initiated and during the procedure it was found that there was extensive vascularity and attachment of the gestational sac to her omentum, mesentery, loops of bowel, lateral pelvic wall, and predominantly her uterine wall. The vascularity was mainly derived from the sacral plexus and the left external iliac artery, and the patient was deemed inoperable due to the high risk of hemorrhage, need for bowel resection, and potential hysterectomy. Consequently, no attempt was made to remove the gestational sac, the placenta was left in situ as well, and the planned fetus removal was deferred to a later date. She was discharged to follow-up at clinic for serial monitoring of her BHCG levels every week, and expectant management. She returned to our ED 11 weeks after feticide with complaints of abdominal pain and vaginal bleeding. A strategic decision was made to bring her to the Operating Room (OR) 2 days later for a second laparotomy, this time with lysis of adhesions, removal of abdominal pregnancy and left salpingo-oophorectomy, which was thought to be the primary site of implantation prior to secondary implantation in her peritoneum. She tolerated the intervention and no adverse or unanticipated event was noted. She was discharged and asked to follow-up with BHCG levels until her levels returned to normal and to return for any further complaints. She adhered to the advice and was counselled not to get pregnant for a year.\n\nTwo years later, she presented to our ED with abdominal pain and nausea. Diagnosis was made of a second ectopic pregnancy in her right fallopian tube, with gestational age corresponding to 6 weeks. She received expectant medical management with methotrexate administration: first dose on the day of presentation, second and third doses, 4 and 7 days after the first methotrexate dose was given. Her BHCG levels were monitored and were seen to trend down from 7026 mIU/ml to 5368 and 3739 and complete resolution of this second ectopic pregnancy was noted. She presented with abdominal pain at our ED approximately 8 months after her second ectopic pregnancy. A TVS confirmed a third ectopic pregnancy, at 5 weeks and 5 days of gestation, adjacent to her right ovary. An exploratory laparotomy was performed with right salpingotomy and ectopic removal after she consented to surgery.\n\nDiscussion\nAbdominal pregnancy (pregnancy in the peritoneal cavity) is a very rare and serious type of extrauterine gestation that accounts for approximately 1.4 % of all ectopic pregnancies [15]; “it also represents one of the few times an ectopic pregnancy can be carried to term” [16]. Early strategic diagnosis and management decisions can make a critical difference with regards to severity of morbidity and mortality risk.\n\nTo the best of our knowledge, our case report represents the first report of an abdominal ectopic pregnancy with a blood supply from the sacral plexus. The consistent clinical presentation of our patient was abdominal pain and nausea, whereas the most common clinical presentation of ectopic pregnancy is early trimester vaginal bleeding and/or abdominal pain [17]. Currently, diagnosis in unruptured ectopic pregnancy is achieved using a combination of transvaginal ultrasonography and measurement of serum BHCG concentrations [11]. Diagnosis can be straightforward when a TVS positively identifies an IUP or ectopic pregnancy [10]. In cases where an ectopic pregnancy is suspected and ultrasound is inconclusive, a diagnostic laparoscopy may be required; this is believed by many to be the ‘gold standard’ investigation in ectopic pregnancy [10]. The patient in our case had all the diagnostic tests, including a laparotomy for the removal of the fetus and the gestational sac during the initial ectopic (abdominal) pregnancy, when she presented with severe abdominal pain. Consequent to the earlier methotrexate administration, repeat abdominal examinations and expectant management, it was thought that the gestational sac, fetus and placenta would continue to be reabsorbed and diminish in volume and complexity, as found at the second laparotomy. The placenta was more easily separated from the sacral plexus and internal iliac vessels with standard surgical procedures, including vascular supply ligation and cautery. “Treatment with pre-operative systemic methotrexate with subsequent laparotomy for removal of the fetus and placenta may minimize potential blood loss, and would be a reasonable approach in the care of a patient with an abdominal pregnancy with placental implantation to the abdominal viscera and blood vessels” [18], as noted here in a 16-week gestation case. During surgery, if the placenta is attached to vital organs it should be left behind [18]. Eleven weeks after the feticide procedure and previous laparotomy, we expected the sac to be completely reabsorbed and eventually not to perform any more invasive procedures. We were surprised at the finding that the products of conception (POC) were not completely reabsorbed and the POC was still at the size of 17 weeks, although it was 11 weeks post-feticide procedure. Reluctance or delay in performing a diagnostic laparoscopy has been highlighted as a factor in fatal cases [19]. The second laparotomy was successful, and on observation of the tubes and uterus, a rupture site was noted on the left tube, which was the reason for the left salpingo-oophorectomy. Post-surgery our patient did well with Hb within normal limits, and no further complaints or complications were noted. A laparotomy should be reserved for patients who present with rupture and are in a state of hypovolemic shock and compromise [11]; however, our patient was deemed unfit for definitive management by laparoscopy because of the extensive vascularity of her placenta from the surrounding structures, and therefore had a laparotomy.\n\nIf BHCG concentrations are falling but an ectopic pregnancy has not been excluded, then consideration should be given to performing serial BHCG measurements until levels become undetectable, as rupture can still occur [20]. Laparoscopic procedures are associated with shorter operative times, less intraoperative blood loss, shorter hospital stays and lower analgesia requirements [21–23], compared to laparotomy.\n\nThe conclusions and recommendations in the “Practice Bulletin, June 2008, Medical Management of Ectopic Pregnancy” of the American Congress of Obstetricians and Gynecologists (ACOG) state that the results of randomized trials in which systemic methotrexate with tube-sparing laparoscopic surgery were compared showed no difference in overall tubal preservation, tubal patency, repeat ectopic pregnancy, or future pregnancies, based on good and consistent evidence. In contrast to tubal ectopic pregnancies, primary methotrexate therapy for early gestation in abdominal pregnancies has had minimal success [24]. This was different to our case, where the second ectopic (6 weeks) was reabsorbed and our patient’s BHCG levels returned to normal after methotrexate treatment. It further suggests that failure of the BHCG level to decrease by at least 15 % from day 4 to day 7 after methotrexate administration is considered treatment failure requiring therapy with either additional methotrexate administration or surgical intervention.\n\nIn our patient, even though her BHCG levels were trending down by 15 % and more with each passing day, a surgical intervention was unavoidable due to the unusual location and unabsorbed gestational sac. The Practice Committee of the American Society for Reproductive Medicine suggested that ovarian and abdominal pregnancies should be diagnosed definitively at the time of surgical exploration, and both conservative surgery and medical therapy may be viewed as appropriate first-line therapies in many early unruptured ectopic pregnancies [25]. As elected in our case, surgical intervention was the initial step in the management of our patient’s ectopic pregnancy.\n\nThe strength of our case report was the strategic approach to management, which included a stepwise combination therapy approach, tailored to the patient’s clinical condition, with some input from her and shared decision making with her.\n\nThere is a 5 to 20 % risk of a recurrence of ectopic pregnancy with one previous ectopic pregnancy and a risk of 32 % or more following more than one previous ectopic pregnancy [11]. The second ectopic pregnancy in our patient was uneventful with medical management and reabsorption of the POC. With regards to her third ectopic pregnancy, she initially refused any interventions and only accepted methotrexate administration on the day of presentation at 5 weeks and 5 days of gestational age, the second dose on day 3 and the third dose on day 7, after her initial dose, with follow-up of BHCG levels every 3 days. However, she returned 10 days later, with right lower quadrant (RLQ) pain and gestational age corresponding to 7 weeks; laparotomy with planned salpingotomy was identified as the best choice after a shared decision-making process. Our patient, an educated African-American woman had access to our hospital and emergency care, was also employed, but without medical insurance. While talking about her experience, she mentioned her financial constraints and the lack of a proper insurance policy, which had impacted her life and her earlier decisions of signing out AMA. Involving social services and encouraging shared decision making with the patient, regarding her procedure choices, her health and her future reproductive life, were critical in the successful outcome of this case.\n\nConclusions\nEctopic pregnancies should be identified early and evaluated for the etiology of the presentation. Rarely, an ectopic pregnancy implants at an extratubal location, such as the cervix, ovary, abdomen, liver, spleen or caesarean section scar [26]. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4 to 10 % of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in subsequent pregnancies [27]. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility [28]. Surgery remains an acceptable, and sometimes necessary, modality for the treatment of ectopic pregnancy [29]. Counselling in these patients, as well as shared decision making, represents an important aspect, as they require a lot of care and understanding of the future risks of similar pregnancies. A careful and strategic choice of management pathway can make all the difference to a favorable outcome.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nAMAAgainst medical advice\n\nBHCGBeta human chorionic gonadotropin\n\nCATComputed axial tomography\n\nEDEmergency Department\n\nHbHemoglobin\n\nIUPIntrauterine pregnancy\n\nMRIMagnetic resonance imaging\n\nPOCProducts of conception\n\nTVSTransvaginal ultrasound scan\n\nCompeting interests\n\nThe authors declare that they have no competing interests. We wish to confirm that there are no known conflicts of interest associated with this publication.\n\nAuthors’ contributions\n\nCP did the search and review of the current medical literature for this manuscript; CP also wrote the initial draft of the manuscript for this case report, guided and supervised by CO. JF reviewed the entire manuscript, suggested changes and edited the manuscript. CO had the concept of the manuscript write up after the case presented to our ED. CO reviewed, edited and proofed the entire case report. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship who are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.\n\nAuthors’ information\n\nChaitali Patel, MD – Emergency Medicine Research Associate, Hackensack University Medical Center.\n\nJoseph Feldman, MD – Chairman of Emergency Medicine, Hackensack University Medical Center.\n\nChinwe Ogedegbe, MD, MPH – Attending Physician and Director of Research Emergency Medicine, Hackensack University Medical Center.\n\nAlthough Dr Patel will remain first author, Dr Ogedegbe will serve as the corresponding author.\n\nAll reviewers work at: Hackensack University Medical Center, 30, Prospect Ave, Hackensack, New Jersey, 07601, USA.\n\nAcknowledgements\nWe wish to confirm that here has been no significant financial support for this work that could have influenced its outcome.\n==== Refs\nReferences\n1. Farquhar CM Ectopic pregnancy Lancet 2005 366 9485 583 91 10.1016/S0140-6736(05)67103-6 16099295 \n2. 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Correspondence: A Practice Committee, American Society for Reproductive Medicine, Birmingham, Alabama; Fertility and Sterility® Vol. 100, No. 3, September 2013 0015-0282; https://www.asrm.org/uploadedFiles/ASRM_Content/News_and_Publications/Practice_Guidelines/Committee_Opinions/optimizing_natural_fertility(1).pdf\n26. Walker JJ Ectopic pregnancy Clin Obstet Gynecol. 2007 50 89 99 10.1097/GRF.0b013e31802f4f79 17304026 \n27. Marion LL Meeks GR Ectopic pregnancy: history, incidence, epidemiology, and risk factors Clin Obstet Gynecol 2012 55 2 376 86 10.1097/GRF.0b013e3182516d7b 22510618 \n28. Juneau C Bates GW Reproductive outcomes after medical and surgical management of ectopic pregnancy Clin Obstet Gynecol 2012 55 2 455 60 10.1097/GRF.0b013e3182510a88 22510628 \n29. Stock L Milad M Surgical management of ectopic pregnancy Clin Obstet Gynecol 2012 55 2 448 54 10.1097/GRF.0b013e3182510a19 22510627\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "10()", "journal": "Journal of medical case reports", "keywords": null, "medline_ta": "J Med Case Rep", "mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008160:Lumbosacral Plexus; D008727:Methotrexate; D010920:Placenta; D011247:Pregnancy; D011269:Pregnancy, Abdominal; D012008:Recurrence", "nlm_unique_id": "101293382", "other_id": null, "pages": "37", "pmc": null, "pmid": "26868918", "pubdate": "2016-02-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12601846;7755078;15640259;8841236;21727242;9091325;8561006;16099295;9075562;19830195;11354843;12543617;19053177;16100636;22510628;10325296;16217116;8798311;22510627;1923258;17304026;17458402;23921671;22510618;16933302", "title": "Complicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4-year follow-up: a case report.", "title_normalized": "complicated abdominal pregnancy with placenta feeding off sacral plexus and subsequent multiple ectopic pregnancies during a 4 year follow up a case report" }

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{ "abstract": "While cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is the most commonly used chemotherapeutic regimen for patients with peripheral T-cell lymphomas (PTCLs), elderly patients are more vulnerable to associated toxicities. We evaluated the efficacy and safety of dose-attenuated CHOP in elderly patients with PTCL.\nPatients with PTCL aged >70 years or 65-70-years with comorbidities were treated with dose-attenuated CHOP (cyclophosphamide: 562.5 mg/m2, doxorubicin: 37.5 mg/m2, vincristine: 1.4 mg/m2, and prednisolone: 100 mg for five days; 25% reduced dose of cyclophosphamide and doxorubicin vs. full-dose CHOP) as first-line therapy were included.\nForty-four patients (median age, 74 yr) were analyzed. The majority (N=42, 95.5%) had advanced stage disease and 36 (81.8%) were classified as high/high-intermediate risk by the international prognostic index. The overall response rate was 61.4%, and 21 patients achieved complete response (47.7%). With median follow-up period of 28.8 months, the estimated two-year progression-free and overall survival rates were 36.7% and 46.6%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 26.9% and 7.4% of 204 total cycles, which affected 76.7% and 25.6% of the patients, respectively. Nineteen patients (44.2%) experienced febrile neutropenia, and six died due to treatment-related toxicities. High lactate dehydrogenase levels and an involvement of >1 extranodal sites were prognostic indicators of poor survival.\nDose-attenuated CHOP does not compromise treatment efficacy but retains significant toxicity. Our results suggest that some patients can be effectively treated with dose-attenuated CHOP, however a novel therapy for elderly patients with PTCL is required.", "affiliations": "Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.", "authors": "Choi|Eun-Ji|EJ|;Hong|Jung Yong|JY|;Yoon|Dok Hyun|DH|;Kang|Jihoon|J|;Park|Chan-Sik|CS|;Huh|Jooryung|J|;Chae|Eun Jin|EJ|;Lee|Yoonse|Y|;Ryu|Jin-Sook|JS|;Suh|Cheolwon|C|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5045/br.2017.52.4.270", "fulltext": "\n==== Front\nBlood ResBlood ResBRBlood research2287-979X2288-0011Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 10.5045/br.2017.52.4.270Original ArticleTreatment outcomes of dose-attenuated CHOP chemotherapy in elderly patients with peripheral T cell lymphoma Choi Eun-Ji 1Hong Jung Yong 2Yoon Dok Hyun 2Kang Jihoon 2Park Chan-Sik 3Huh Jooryung 3Chae Eun Jin 4Lee Yoonse 5Ryu Jin-Sook 6Suh Cheolwon 21 Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.4 Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.5 Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.6 Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.\nCorrespondence to Cheolwon Suh, M.D., Ph.D. Department of Oncology, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. csuh@amc.seoul.kr\nCorrespondence to Dok Hyun Yoon, M.D., Ph.D. Department of Oncology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. dhyoon@amc.seoul.kr12 2017 26 12 2017 52 4 270 275 25 4 2017 13 5 2017 25 6 2017 © 2017 Korean Society of Hematology2017Korean Society of HematologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nWhile cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is the most commonly used chemotherapeutic regimen for patients with peripheral T-cell lymphomas (PTCLs), elderly patients are more vulnerable to associated toxicities. We evaluated the efficacy and safety of dose-attenuated CHOP in elderly patients with PTCL.\n\nMethods\nPatients with PTCL aged >70 years or 65–70-years with comorbidities were treated with dose-attenuated CHOP (cyclophosphamide: 562.5 mg/m2, doxorubicin: 37.5 mg/m2, vincristine: 1.4 mg/m2, and prednisolone: 100 mg for five days; 25% reduced dose of cyclophosphamide and doxorubicin vs. full-dose CHOP) as first-line therapy were included.\n\nResults\nForty-four patients (median age, 74 yr) were analyzed. The majority (N=42, 95.5%) had advanced stage disease and 36 (81.8%) were classified as high/high-intermediate risk by the international prognostic index. The overall response rate was 61.4%, and 21 patients achieved complete response (47.7%). With median follow-up period of 28.8 months, the estimated two-year progression-free and overall survival rates were 36.7% and 46.6%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 26.9% and 7.4% of 204 total cycles, which affected 76.7% and 25.6% of the patients, respectively. Nineteen patients (44.2%) experienced febrile neutropenia, and six died due to treatment-related toxicities. High lactate dehydrogenase levels and an involvement of >1 extranodal sites were prognostic indicators of poor survival.\n\nConclusion\nDose-attenuated CHOP does not compromise treatment efficacy but retains significant toxicity. Our results suggest that some patients can be effectively treated with dose-attenuated CHOP, however a novel therapy for elderly patients with PTCL is required.\n\nPeripheral T cell lymphomaElderlyDose-attenuated CHOP\n==== Body\nINTRODUCTION\nPeripheral T cell lymphoma (PTCL) represents a group of heterogeneous lymphoproliferative disorders arising from the clonal expansion of post-thymic T cells or natural killer (NK) cells [1]. While PTCL is a relatively uncommon disease, which accounts for <20% of all non-Hodgkin lymphoma (NHL) cases, the prevalence of PTCL in Asian countries is higher than in the West [23]. The clinical course of PTCLs is typically aggressive and associated with poor prognosis with five-year overall survival (OS) rates below 30% [3456].\n\nThe median age for PTCL development was reported to be 62 years in the international T-cell lymphoma projects, and according to SEER data, approximately 40% of patients with PTCL are above the age of 70 years [37]. Moreover, elderly patients have a poor tolerance to chemotherapy due to impaired bone marrow (BM) function, altered drug metabolism, and presence of comorbid diseases. Thus, elderly patient with PTCL often suffer from increased susceptibility to treatment-related complications [68].\n\nAlthough there is no consensus based on randomized trials regarding an optimal first-line chemotherapy for PTCLs, anthracycline-based CHOP-like regimens have been the most common treatment. However, optimal dosing for elderly patients has not been specifically addressed. In this study, we attempted to reduce the dose of two myelotoxic agents (cyclophosphamide and doxorubicin) by 25% from the full-dose CHOP regimen, with the aim of decreasing chemotherapy-related hematologic and/or infectious complications in elderly patients. We assessed the efficacy and safety of a dose-attenuated CHOP regimens in patients with PTCL aged over 70 years and those aged between 65–70-year with comorbidities that were either expected to result in significant treatment-related toxicities or included in the parameters of a comprehensive geriatric assessment.\n\nMATERIALS AND METHODS\nPatient population\nThe data of 44 consecutive elderly patients with PTCL were used for analysis in this study. We included patients aged between 65 and 70 years, with comorbidities that were expected to result in significant treatment-related toxicities or included in the parameters of a comprehensive geriatric assessment [such as heart failure (NYHA III-IV), coronary artery disease, cardiac arrhythmia, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, renal insufficiency (creatinine clearance ≤50 mL/min), cirrhosis, post-stroke neurologic sequelae, and/or medically unfit condition] [910], and patients aged over 70 years who were treated with dose-attenuated CHOP chemotherapy between April 2001 and 2015. All patients underwent pre-treatment heart scan or transthoracic echocardiography, and those with significant cardiac dysfunction were excluded due to risk of anthracycline cardiotoxicity. Diagnosis of PTCL was confirmed by a certified hematopathologist, according to World Health Organization (WHO) criteria [11]. We excluded patients with extranodal NK/T cell lymphoma, nasal-type (ENKTL) or adult T cell leukemia/lymphoma, and those who had previously received other chemotherapeutic agents for lymphoma. The study protocol was approved by the Institutional Review Board (2016-0568) in accordance with the 2008 Declaration of Helsinki.\n\nDisease evaluation\nAll patients were staged according to the Lugano classification at the time of diagnosis based on results of their medical history, physical examination, complete blood count, serum lactate dehydrogenase (LDH), computed tomography (CT), BM aspiration and biopsy, and a positron emission tomography-CT (PET-CT) scan [12]. Response to treatment was assessed after four and six cycles of dose-attenuated CHOP chemotherapy or whenever progressive disease was suspected based on international criteria [13]. Hematologic and major treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.\n\nTreatment\nThe dose-attenuated CHOP regimen consisted of 562.5 mg/m2 cyclophosphamide administered intravenously for one day (25% reduction from full-dose CHOP), 37.5 mg/m2 doxorubicin for one day (25% reduction from full-dose CHOP), 1.4 mg/m2 vincristine for one day, and 50 mg prednisolone twice a day for five days. Patients were scheduled to receive six cycles of dose-attenuated CHOP at three-week intervals, however the treatment interval could be modified at the physician's discretion after considering blood count recovery or the patients' general condition. Primary prophylactic pegylated granulocyte-colony stimulating factor (peg-G-CSF) was routinely administered to nine patients treated since August 2014, when peg-G-CSF was reimbursed by national health insurance. In the event of severe neutropenia or febrile neutropenic events, G-CSF was administered subcutaneously to patients who were not given prophylactic peg-G-CSF. The dose of cyclophosphamide and doxorubicin was reduced by an additional 25% if the ANC and platelet counts did not recover to less than grade 1, even after a two-week delay, or according to physician discretion.\n\nStatistical analysis\nOverall survival (OS) was calculated from the date of the diagnosis to the date of last follow-up or death due to any cause. Progression-free survival (PFS) was defined as the duration from the date of diagnosis to the date of progression, relapse, or death from any cause. Efficacy analyses were performed using the intention-to-treat principle. Survival was calculated using the Kaplan–Meier method and analyzed using a log-rank test for univariate analysis and a Cox regression model for multivariate analysis. Variables with P<0.1 in the univariate analysis were selected for the multivariate analysis models. Two-sided P<0.05 was considered statistically significant.\n\nRESULTS\nPatient characteristics\nCharacteristics of the 44 elderly patients with PTCL are summarized in Table 1. The diagnoses included PTCL-not otherwise specified (NOS) (N=27), angioimmunoblastic T cell lymphoma (N=9), anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (N=5), and enteropathy-associated T cell lymphoma (N=3). The median age at diagnosis was 74 years (range, 65–86 yr). Of the 15 patients aged between 65 and 70 years, there were three with diabetes mellitus and hypertension, one with diabetes mellitus and angina, three who had an immobilized status associated with a compression fracture, one with arrhythmia (atrial fibrillation), one with liver cirrhosis, one with post-stroke neurologic sequelae, one with myelodysplastic syndrome, one with major depression, one with chronic lung disease, one with poor nutritional status with post-op leakage after small bowel resection, and one with panhypopituitarism. Three patients were identified as positive for hepatitis B surface antigen before treatment, two of whom were already on treatment with entecavir and the other one was given prophylactic tenofovir with chemotherapy. Most patients displayed an advanced disease stage (95.5%), and 36 (81.8%) patients were categorized as high-intermediate or high risk according to the International Prognostic Index (IPI) scoring system [14]. According to the Prognostic Index for PTCL-U (PIT), which includes age, Eastern Cooperative Oncology Group performance status (ECOG PS), LDH level, and BM involvement, 79.5% of the patients were classified into a high-risk group (PIT score>2) [4].\n\nResponse to treatment\nOf the 44 patients in the intention-to-treat population, 23 (52.3%) patients completed the six scheduled cycles of treatment. The causes of discontinuation included chemo-refractory or progressive disease within three cycles (N=11), infection (N=6), subdural hemorrhage (N=1), and intolerance (N=2), and one patient was lost to follow-up. Relative dose intensity for the 23 patients who completed treatment was 72.4±13.7% for both doxorubicin and cyclophosphamide. The response to treatment was assessable in 35 patients both during and at the end of treatment, however nine patients died or were lost to follow-up before the post-treatment evaluation. A total of 21 patients achieved complete response (CR) and six achieved partial response (PR); thus, the overall response rate (ORR) and CR rate were 61.4% and 47.7%, respectively. Of the 21 complete responders, 11 remained in remission for a median duration of 14.3 months (range, 1.4–158.1 mo), however 9 of the 21 complete responders and four of the six partial responders experienced disease relapse or progression after completing treatment. Of the other two patients who achieved PR, one died of pneumonia with septic shock 12 days after achieving PR, following three cycles of the chemotherapy, and the other was lost to follow-up four months after completion of six chemotherapy cycles.\n\nSurvival\nDuring the median follow-up duration for survivors (28.8 mo, range, 7.1–174.6 mo), 23 patients experienced disease progression and 23 patients died. The estimated two-year PFS and OS rates were 36.7% (95% CI: 27.9–45.5%) and 46.6% (95% CI: 37.7–53.3%), and the median PFS and OS were 8.2 and 11.7 months, respectively (Fig. 1). Of the 23 deaths, 16 were secondary to lymphoma progression, six were related to treatment toxicities (five infections and one bleeding), and one was due to an unknown cause.\n\nOf the 27 responders, 20 remained alive at the time of the analysis, whereas only one of eight non-responders survived. The surviving patient who did not respond to dose-attenuated CHOP received four cycles of gemcitabine-based cytotoxic chemotherapy (gemcitabine, dexamethasone, and cisplatin) as salvage treatment, achieved CR, and remained alive at the time of the analysis without evidence of disease. Thirteen patients survived for more than 48 months at the time of analysis, and these long-term survivors showed tendencies toward better performance status (ECOG PS 2–4 of 7.7% vs. 30.2%, P=0.1), less advanced stage (Ann Arbor stage III-IV of 76.9% vs. 100%, P=0.001), and less extranodal disease (>1 extranodal sites of 38.5% vs. 62.8%, P=0.120) than short-term survivors at baseline. In addition, long-term survivors had higher CR rates (92.3% vs. 39.5%, P=0.004) and experienced less grade 3 or 4 thrombocytopenia (0% vs. 35%, P=0.013) and neutropenia (61.5% vs. 82.5%, P=0.117). In the univariate analysis, ECOG PS >1 (P=0.023), high IPI score (P=0.043), and high PIT score (P=0.028) were associated with inferior PFS (Table 2). Patients with ECOG PS >1 (P=0.019), high LDH level (P=0.013), or disease involvement of >1 extranodal sites (P=0.003) had a shorter OS duration (Table 2). The Cox-regression model analysis revealed that poor ECOG PS [hazard ratio (HR): 5.14; 95% CI: 1.52–17.45; P=0.009] remained an independent prognostic factor for shorter PFS. The involvement of more than one extranodal site (HR: 4.78; 95% CI: 1.76–12.98; P=0.002) and a high LDH level (HR: 2.91; 95% CI: 1.08–7.87; P=0.035) were independent prognostic factors of inferior OS (Table 3).\n\nTreatment toxicity\nHematologic toxicities were evaluable in 43 of the 44 patients; one patient was lost to follow-up after the first cycle of chemotherapy. Grade 3 or 4 neutropenia was observed after 55 (26.9%) of the 204 total administered cycles, which affected 33 (76.7%) of 43 patients. Of these 55 neutropenic events, 42 (76.4%) occurred within the second cycle of chemotherapy. A total of 19 (44.2%) patients experienced febrile neutropenia during treatment, and three died of infectious complications. Grade 3 or 4 thrombocytopenia occurred after 15 (7.4%) out of 204 total cycles, which affected 11 (25.6%) of 43 patients. Although the difference was not significant, patients with BM involvement at the time of diagnosis experienced more severe neutropenia after chemotherapy, which was denoted by nadir ANC median counts of 345/µL with BM involvement, and 601/µL without BM involvement (P=0.074). Further dose reduction was necessary for 16 of 44 patients (36.4%) due to severe neutropenia that resulted in febrile neutropenic episodes. Among the nine patients who received primary prophylactic peg-G-CSF, seven (77.8%) and three (33.3%) patients experienced grade 3 or 4 neutropenia and febrile neutropenia, respectively. Of the 35 patients who did not receive prophylactic peg-G-CSF, 28 (80.0%) and 16 (45.7%) experienced grade 3 or 4 neutropenia and febrile neutropenia, respectively (P=0.754 for grade 3 or 4 neutropenia; P=0.461 for febrile neutropenia).\n\nThe most common non-hematologic serious adverse events were infections, and five patients (11.4%) experienced grade 3 or 4 infectious complications. Among these five patients, four died from septic shock within 28 days after the first cycle of chemotherapy. Five patients (11.4%) experienced grade 2 or higher sensory neuropathy during treatment, and one suffered from persistent cytopenia and a subdural hemorrhage, six weeks after the second cycle.\n\nDISCUSSION\nIn our study, we evaluated the outcomes of dose-attenuated CHOP chemotherapy for elderly PTCLs, which resulted in an ORR of 61.4%, CR rate of 47.7%, two-year PFS rate of 36.7%, and OS of 46.6%. These results appear comparable to those of previous studies involving full-dose CHOP chemotherapy that covered a 21-day interval. In the NHL-B2 trial of the DSHNHL, patient with B- and T-cell NHL aged between 61 and 75 years exhibited a CR rate of 60.1%, three-year event-free survival of 41.3%, and three-year OS of 48.8% [15]. In the GOELAMs-LTP95 prospective randomized study of PTCL, which compared VIP-reinforced ABVD with CHOP-21, 69% of patients were aged over 60 years, and the CR and two-year PFS rates in the CHOP group were 35% and 41%, respectively [16]. Recent multicenter data from South East Korea assessing the efficacy of various regimens, such as CHOP, CHOEP, IMEP, and CVP, in elderly patients with PTCL also reported an ORR of 70.2% with a CR rate of 37.8%, and the estimated five-year PFS and OS rates were 16.6% and 45.9%, respectively, which are similar to our results [17].\n\nIn the present study, a dose reduction of doxorubicin and cyclophosphamide failed to mitigate the toxicities associated with CHOP chemotherapy in elderly patients. The reduced treatment dose was still associated with elevated rates of hematologic toxicities, including grade 3 or 4 neutropenia and febrile neutropenic events in 76.7% and 44.2% of patients, respectively. This high rate of neutropenia was similar to the rate of 72.1% exhibited in the three-weekly CHOP arm of the NHL-B2 trial of DSHNHL [15]. In the GOELAMS-LTP95 trial, grade 3/4 neutropenia and thrombocytopenia episodes were observed in 8.3% and 1.6% of all cycles, respectively, with treatment-related deaths occurring in 6.7% of patients [16]. These might be attributed to reduced hematopoietic reserve, decreased hepatic and renal function associated with drug metabolism and excretion, changes in physiological body composition related to increased toxicity, and emotional frailty of elderly patients [18]. In the present study, 19 (43.2%) of the 44 patients had lymphoma with BM involvement at the time of diagnosis, and this incidence was much higher than the 3% to 29% rates of common PTCL subtypes obtained from an international PTCL study [3]. A Chinese study involving 56 patients with PTCL patients who were over 60 years in age also reported a substantially smaller proportion of BM involvement, at 7.0% [19]. Our results suggest that this high rate of BM involvement at least partially explains the higher frequencies of grade 3 or 4 neutropenia and febrile neutropenia events observed in our study. Old age is generally considered a risk factor for higher rates of neutropenic infections following CHOP treatment or CHOP-like regimens [2021], and several controlled trials and meta-analyses have revealed that the prophylactic use of peg-G-CSF reduces the occurrence of febrile neutropenic events [2223]. Although the present study included nine patients who received primary prophylactic peg-G-CSF, no significant differences in grade 3 or 4 neutropenia and febrile neutropenia were noted during the routine administration of prophylactic G-CSF, which could be attributed to the small number of patients in our study. In addition, six patients died of therapy-related toxicities without disease progression, which yielded a slightly higher treatment-related mortality rates (13.6%) than observed in the two previous studies: 7% in the GOELAMS-LTP95 trial and 3.4% in the three weekly CHOP arm of the NHL-B2 trial of DSHNHL. However, this difference requires cautious interpretation because patients from the NHL-B2 trial of DSHNHL had far better baseline patient characteristics than that of our study cohort, including substantially lower rates of BM involvement (12.9%), advanced stage (53.4%), IPI-high risk (25.3%), and extranodal sites >1 (30.9%).\n\nThe major limitations of our study include its retrospective nature and small sample size. Our approach did not include a steroid prephase, which is advocated by the German high-grade lymphoma study group and might increase patient tolerability to chemotherapy [18]. Despite these limitations, our results address a very important question pertaining to the proper dose of CHOP chemotherapy for frail elderly patients. It is especially noteworthy that the regimen did not compromise efficacy despite the dose reduction, which suggests that at least some patients can be treated with reduced dose CHOP without compromising the efficacy of this therapy. We believe that full-dose chemotherapy is not mandatory in frail elderly populations, as the outcomes of intensive chemotherapies were not more favorable than those of CHOP therapy in the MDACC study [24] or a separate randomized trial [16]. In theory, through effectively separating these two populations of patients, we may be able to discover trends towards better performance status, early stage disease, and less involvement of extranodal disease in long-term survivors.\n\nIn conclusion, the efficacy of dose-attenuated CHOP appears comparable to that of full-dose CHOP chemotherapy in elderly patients. The short duration of response with frequent relapses and a high toxicity rates remain serious shortcomings associated with this regimen. However, we identified a subgroup of long-term survivors with durable responses and strategies are required to effectively identify such patients. In addition, safer and more effective novel therapeutic approaches for elderly populations are urgently needed.\n\nAuthors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.\n\nFig. 1 Survival curves. (A) The estimated two-year progression-free survival rate was 36.7% and (B) the two-year overall survival rate was 46.6%.\nTable 1 Patient characteristics.\nAbbreviations: AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; EATL, enteropathy-associated T-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase; PIT, Prognostic Index for PTCL-U; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; WHO, World Health Organization.\n\nTable 2 Univariate analysis of prognostic factors.\nAbbreviations: AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; BM, bone marrow; EATL, enteropathy-associated T-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PIT, Prognostic Index for PTCL-U; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; WHO, World Health Organization.\n\nTable 3 Multivariate analysis of prognostic factors.\nAbbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; NA, not applicable; NS, not significant; OS, overall survival; PFS, progression-free survival.\n==== Refs\n1 Savage KJ Harris NL Vose JM ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project Blood 2008 111 5496 5504 18385450 \n2 Anderson JR Armitage JO Weisenburger DD Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project Ann Oncol 1998 9 717 720 9739436 \n3 Vose J Armitage J Weisenburger D International T-Cell Lymphoma Project International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes J Clin Oncol 2008 26 4124 4130 18626005 \n4 Gallamini A Stelitano C Calvi R Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study Blood 2004 103 2474 2479 14645001 \n5 Weisenburger DD Savage KJ Harris NL Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project Blood 2011 117 3402 3408 21270441 \n6 Schmitz N Trümper L Ziepert M Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group Blood 2010 116 3418 3425 20660290 \n7 Adams SV Newcomb PA Shustov AR Racial patterns of peripheral T-cell lymphoma incidence and survival in the United States J Clin Oncol 2016 34 963 971 26962200 \n8 Peyrade F Jardin F Thieblemont C Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial Lancet Oncol 2011 12 460 468 21482186 \n9 Extermann M Hurria A Comprehensive geriatric assessment for older patients with cancer J Clin Oncol 2007 25 1824 1831 17488980 \n10 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology. Older Adult Oncology Fort Washington, PA National Comprehensive Cancer Network 2016 Accessed April 11, 2017 at https://www.nccn.org/professionals/physician_gls/pdf/senior.pdf \n11 Swerdlow SH Campo E Harris NL WHO classification of tumours of haematopoietic and lymphoid tissues 4th ed Lyon, France IARC Press 2008 \n12 Cheson BD Fisher RI Barrington SF Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification J Clin Oncol 2014 32 3059 3068 25113753 \n13 Cheson BD Pfistner B Juweid ME Revised response criteria for malignant lymphoma J Clin Oncol 2007 25 579 586 17242396 \n14 International Non-Hodgkin's Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin's lymphoma N Engl J Med 1993 329 987 994 8141877 \n15 Pfreundschuh M Trümper L Kloess M Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL Blood 2004 104 634 641 15016643 \n16 Simon A Peoch M Casassus P Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95 Br J Haematol 2010 151 159 166 20738307 \n17 Jo JC Choi Y Shin HJ Peripheral T cell lymphomas in elderly patients: a retrospective analysis from the Hematology Association of South East Korea (HASEK) Ann Hematol 2016 95 619 624 26779714 \n18 Pfreundschuh M How I treat elderly patients with diffuse large B-cell lymphoma Blood 2010 116 5103 5110 20805363 \n19 Zhao H Wang T Wang Y Comorbidity as an independent prognostic factor in elderly patients with peripheral T-cell lymphoma Onco Targets Ther 2016 9 1795 1799 27069369 \n20 Bastion Y Blay JY Divine M Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival-a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years J Clin Oncol 1997 15 2945 2953 9256139 \n21 Bertini M Freilone R Vitolo U The treatment of elderly patients with aggressive non-Hodgkin's lymphomas: feasibility and efficacy of an intensive multidrug regimen Leuk Lymphoma 1996 22 483 493 8882962 \n22 Grigg A Solal-Celigny P Hoskin P Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin's lymphoma Leuk Lymphoma 2003 44 1503 1508 14565651 \n23 Lyman GH Kuderer N Agboola O Balducci L Evidence-based use of colony-stimulating factors in elderly cancer patients Cancer Control 2003 10 487 499 14652525 \n24 Escalón MP Liu NS Yang Y Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M.D. Anderson Cancer Center experience Cancer 2005 103 2091 2098 15816054\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2287-979X", "issue": "52(4)", "journal": "Blood research", "keywords": "Dose-attenuated CHOP; Elderly; Peripheral T cell lymphoma", "medline_ta": "Blood Res", "mesh_terms": null, "nlm_unique_id": "101605247", "other_id": null, "pages": "270-275", "pmc": null, "pmid": "29333403", "pubdate": "2017-12", "publication_types": "D016428:Journal Article", "references": "8141877;20660290;15016643;8882962;17242396;25113753;26962200;15816054;18385450;9256139;18626005;9739436;27069369;14565651;14645001;20738307;14652525;20805363;17488980;21270441;26779714;21482186", "title": "Treatment outcomes of dose-attenuated CHOP chemotherapy in elderly patients with peripheral T cell lymphoma.", "title_normalized": "treatment outcomes of dose attenuated chop chemotherapy in elderly patients with peripheral t cell lymphoma" }

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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. 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TREATMENT OUTCOMES OF DOSE-ATTENUATED CHOP CHEMOTHERAPY IN ELDERLY PATIENTS WITH PERIPHERAL T CELL LYMPHOMA. BLOOD RESEARCH. 2017?52 (4):270-275", "literaturereference_normalized": "treatment outcomes of dose attenuated chop chemotherapy in elderly patients with peripheral t cell lymphoma", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20180109", "receivedate": "20180109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14368030, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]

{ "abstract": "BACKGROUND Epinephrine for anaphylactic shock is the standard life-saving treatment in the emergency department. Cardiac symptoms after epinephrine administration in a child with no prior cardiac history are often not suspected. We describe a presentation of diastolic cardiac dysfunction after anaphylaxis from a bee sting in an adolescent male. CASE REPORT A 16-year-old male with no prior history of allergy presented with anaphylaxis following a bee sting. The patient received an inadvertent intravenous rather than intramuscular dose of 1: 1000 epinephrine, leading to myocardial ischemia. Diastolic dysfunction resulting from myocardial ischemia and fluid resuscitation led to development of pulmonary edema. The patient required epinephrine drip for hemodynamic support and BiPAP for respiratory support. CONCLUSIONS This case highlights the risk of giving a rapid intravenous push of epinephrine, which converted an anaphylactic reaction to cardiogenic shock. Anaphylaxis-related coronary ischemia (Kounis) syndrome is another less likely etiology for our patient's presentation.", "affiliations": "Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Cardiology, Children's Hospital of Illinois, Peoria, IL, USA.;Division of Pediatric Critical Care, Children's Hospital of Illinois, Peoria, IL, USA.", "authors": "Tripathi|Sandeep|S|;Kulikowska|Agnieszka|A|;Patel|Priti M|PM|;Hassan|Nabil E|NE|", "chemical_list": "D014662:Vasoconstrictor Agents; D004837:Epinephrine", "country": "United States", "delete": false, "doi": "10.12659/AJCR.922120", "fulltext": null, "fulltext_license": null, "issn_linking": "1941-5923", "issue": "21()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000293:Adolescent; D000707:Anaphylaxis; D000818:Animals; D001516:Bees; D004562:Electrocardiography; D004837:Epinephrine; D006801:Humans; D007275:Injections, Intravenous; D007299:Insect Bites and Stings; D008297:Male; D017202:Myocardial Ischemia; D011654:Pulmonary Edema; D012770:Shock, Cardiogenic; D014662:Vasoconstrictor Agents", "nlm_unique_id": "101489566", "other_id": null, "pages": "e922120", "pmc": null, "pmid": "32467557", "pubdate": "2020-05-29", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute Myocardial Ischemia Following Bee Sting in an Adolescent Male: A Case Report.", "title_normalized": "acute myocardial ischemia following bee sting in an adolescent male a case report" }

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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "50 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD BITE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENADRYL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL ISCHAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN (E.C.)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MG OF 1: 1000 EPINEPHRINE BY RAPID PUSH", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALLERGY TO ARTHROPOD STING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "56.7", "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diastolic dysfunction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myocardial ischaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TRIPATHI, S.. ACUTE MYOCARDIAL ISCHEMIA FOLLOWING BEE STING IN AN ADOLESCENT MALE: A CASE REPORT. 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{ "abstract": "BACKGROUND Pancreatic metastasis from colorectal cancer is rare and can masquerade as primary pancreatic cancer. CASE REPORT A 70-year-old male was diagnosed with advanced rectal cancer with multiple liver metastases. After neoadjuvant chemotherapy, he underwent radical surgery for the primary tumor and hepatectomy for multiple liver metastases. Adjuvant chemotherapies and additional surgeries were subsequently required for recurrences in the liver, lung, and lymph nodes. A diffuse hypovascular nodule in the pancreatic head and a solitary liver metastasis were detected 2.5 years after the initial surgery and he accordingly underwent further chemotherapy. However, the pancreatic tumor progressed, invading the pancreatic duct and biliary tract. Obstructive jaundice finally prompted discontinuation of chemotherapy and he underwent biliary drainage. His diffuse and hypovascular tumor was clinically and radiographically diagnosed as a primary pancreatic cancer. Pancreatic resection for the pancreatic tumor and hepatectomy for the liver metastasis were performed 4.2 years after the initial surgery, achieving radiographic and surgical curative resection. Pathological examination of the surgical specimen resulted in a definitive diagnosis of metachronous pancreatic metastasis from his primary rectal cancer. Despite further chemotherapy, his general condition worsened; however, he remains alive 5.4 years after the initial surgery, with best supportive care. CONCLUSIONS Pancreatic metastasis originating from rectal cancer can masquerade as primary pancreatic cancer clinically and radiologically. Multimodality treatment is mandatory for metastatic colorectal cancer. Aggressive surgeries for pancreatic metastasis should be considered if curative resection appears possible radiographically and/or intraoperatively.", "affiliations": "Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.;Department of Surgery, Shiga General Hospital, Moriyama, Shiga, Japan.", "authors": "Tani|Ryotaro|R|;Hori|Tomohide|T|;Yamada|Masahiro|M|;Yamamoto|Hidekazu|H|;Harada|Hideki|H|;Yamamoto|Michihiro|M|;Yazawa|Takefumi|T|;Tani|Masaki|M|;Kamada|Yasuyuki|Y|;Aoyama|Ryuhei|R|;Sasaki|Yudai|Y|;Zaima|Masazumi|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.12659/AJCR.918669", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3178450310.12659/AJCR.918669918669ArticlesMetachronous Pancreatic Metastasis from Rectal Cancer that Masqueraded as a Primary Pancreatic Cancer: A Rare and Difficult-to-Diagnose Metastatic Tumor in the Pancreas Tani Ryotaro BCD*Hori Tomohide ACDEF*Yamada Masahiro BCDYamamoto Hidekazu FHarada Hideki FYamamoto Michihiro FYazawa Takefumi FTani Masaki FKamada Yasuyuki FAoyama Ryuhei FSasaki Yudai FZaima Masazumi ADFDepartment of Surgery, Shiga General Hospital, Moriyama, Shiga, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Ryotaro Tani and Tomohide Hori contributed equally to this work\n\nConflict of interest: None declared\n\nCorresponding Author: Tomohide Hori, e-mail: horitomo55office@yahoo.co.jp2019 30 11 2019 20 1781 1787 11 7 2019 24 9 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 70\n\nFinal Diagnosis: Metachronous pancreatic metastasis\n\nSymptoms: None\n\nMedication: —\n\nClinical Procedure: Surgery\n\nSpecialty: Gastroenterology and Hepatology\n\nObjective:\nRare disease\n\nBackground:\nPancreatic metastasis from colorectal cancer is rare and can masquerade as primary pancreatic cancer.\n\nCase Report:\nA 70-year-old male was diagnosed with advanced rectal cancer with multiple liver metastases. After neoadjuvant chemotherapy, he underwent radical surgery for the primary tumor and hepatectomy for multiple liver metastases. Adjuvant chemotherapies and additional surgeries were subsequently required for recurrences in the liver, lung, and lymph nodes. A diffuse hypovascular nodule in the pancreatic head and a solitary liver metastasis were detected 2.5 years after the initial surgery and he accordingly underwent further chemotherapy. However, the pancreatic tumor progressed, invading the pancreatic duct and biliary tract. Obstructive jaundice finally prompted discontinuation of chemotherapy and he underwent biliary drainage. His diffuse and hypovascular tumor was clinically and radiographically diagnosed as a primary pancreatic cancer. Pancreatic resection for the pancreatic tumor and hepatectomy for the liver metastasis were performed 4.2 years after the initial surgery, achieving radiographic and surgical curative resection. Pathological examination of the surgical specimen resulted in a definitive diagnosis of metachronous pancreatic metastasis from his primary rectal cancer. Despite further chemotherapy, his general condition worsened; however, he remains alive 5.4 years after the initial surgery, with best supportive care.\n\nConclusions:\nPancreatic metastasis originating from rectal cancer can masquerade as primary pancreatic cancer clinically and radiologically. Multimodality treatment is mandatory for metastatic colorectal cancer. Aggressive surgeries for pancreatic metastasis should be considered if curative resection appears possible radiographically and/or intraoperatively.\n\nMeSH Keywords:\nColorectal NeoplasmsNeoplasm MetastasisPancreasRectal Neoplasms\n==== Body\nBackground\nThere are various types of primary cancers of the pancreas, some of which are rare [1]. Invasive ductal carcinoma, the most common type of primary pancreatic cancer [1], usually shows as a diffuse and hypovascular nodule in imaging studies. Infiltrating carcinoma is often accompanied by invasions of the blood vessels, biliary tract, and pancreatic duct. Obstructive jaundice and associated pancreatitis frequently complicate invasive tumors located in the pancreatic head [1].\n\nMetastases to the pancreas account for approximately 2% of pancreatic neoplasms [2]. Pancreatic metastases from colorectal cancer are rare [3–14], and acceptable outcomes can be achieved by curative resection in carefully selected patients [5,6,8,10,12–15]. Treatment guidelines recommend aggressive resection of hematogenous metastases (i.e., lung or liver metastases) [16,17] if radiographic and/or surgical R0 (i.e., radiographic/surgical R0 resection, according to the Japanese Classification of Colorectal, Appendiceal and Anal carcinoma [18]) is accomplished [5,7–10,12,13,15–17]. Whether pancreatic metastases occur via hematogenous pathways is controversial [7–10,12]. Aggressive surgery should be a component of multimodality treatment of metastatic colorectal cancer [5,6,8–10,12–17].\n\nHere, we report a rare and misdiagnosed case of pancreatic metastasis originating from rectal cancer. Imaging findings resembled those of primary pancreatic cancer. We also discuss the role of surgical resection in treatment of this rare metastasis.\n\nCase Report\nA 70-year-old male visited our hospital with symptoms of bowel obstruction. Colorectal endoscopy, pathological diagnosis based on biopsy specimen, and enhanced computed tomography were performed as initial diagnostic workup. Detailed examination resulted in a clinical diagnosis of advanced rectal cancer with multiple liver metastases. He underwent neoadjuvant chemotherapy with 3 courses of 5-fluorouracil plus oxaliplatin followed by 2 courses of panitumumab followed by laparoscopic low anterior resection with intentional lymphadenectomy. Partial hepatectomy and left lobectomy were also performed for multiple liver metastases. According to imaging studies and surgical findings, curative resection was achieved (i.e., radiographic/surgical R0 resection [18]). The final pathological diagnosis was T4aN1aM1a stage IVA (TNM classification [19]) well-differentiated tubular adenocarcinoma. Adjuvant chemotherapy with 6 courses of 5-fluorouracil plus oxaliplatin was completed. One year after the initial surgery, lymphadenectomy for recurrent metastatic lymph nodes was required, achieving radiographic/surgical R0 [18]; thereafter, further chemotherapy with capecitabine plus panitumumab was administered. Subsequently, right lower lobectomy was performed for a solitary lung metastasis and chemotherapy discontinued for 7 months because radiographic/surgical R0 [18] had been achieved. A solitary liver metastasis and lymphoid metastases were then detected; these resolved radiographically after recommencing chemotherapy with 5-fluorouracil, oxaliplatin and panitumumab. This was discontinued once radiographic R0 [18] had again been achieved, and then resumed after detection of another solitary liver metastasis and lymphoid metastasis. Oxaliplatin was omitted from his regimen because of refractory peripheral neuropathy. Four cycles of chemotherapy with 5-fluorouracil plus leucovorin were administered, achieving radiological resolution of these metastases (radiographic R0 [18]). At 2.5 years after the initial surgery, a further solitary liver metastasis and a diffuse hypovascular nodule in the pancreatic head were detected (Figure 1). Further chemotherapy with 5-fluorouracil, irinotecan and bevacizumab was administered for 1.6 years, and then discontinued because of development of progressive obstructive jaundice caused by the pancreatic tumor. Radiographic and ultrasonography details of this pancreatic neoplasm are shown in Figures 2–4. The tumor was in the pancreatic head, hypovascular, and 21×19 mm in size (Figures 1, 2). Diffuse invasion of the pancreatic duct and biliary tract resulted in obstruction and remarkable dilation of the distal pancreatic duct, intrahepatic bile ducts, and extrahepatic biliary tract (Figures 3, 4). Biliary drainage was achieved via an endoscopic nasobiliary drainage tube (Figure 4). Pathological examination of a biopsy specimen resulted in a diagnosis of moderately-differentiated tubular adenocarcinoma. It was difficult to make a definitive diagnosis of our patient’s locally advanced pancreatic tumor; however, we concluded on the basis of the clinical and radiographic evidence that it was a primary pancreatic cancer rather than a metachronous metastasis from the original rectal cancer. At 4.2 years after the initial surgery, subtotal stomach-preserving pancreaticoduodenectomy for the pancreatic tumor and partial hepatectomy for the solitary liver metastasis were performed, achieving radiographic/surgical R0 resection [18]. Pathological examination revealed that the pancreatic tumor was similar to the original rectal cancer (Figure 5); furthermore, the pancreatic neoplasm lacked the typical pathological features (e.g., not a tubular adenocarcinoma) of primary pancreatic cancer. Immunohistological studies revealed negativity for cytokeratin 7 and positivity for cytokeratin 20 and caudal type homeobox transcription factor 2 (Figure 6). These findings resulted in a definitive pathological diagnosis of metachronous pancreatic metastasis originating from our patient’s primary rectal cancer. A total of 6 courses of chemotherapy with 5-fluorouracil, panitumumab and leucovorin were given; however, multiple liver metastases appeared. His general condition worsened despite further chemotherapy with 5-fluorouracil, panitumumab and leucovorin and with 5-fluorouracil, irinotecan and bevacizumab. Although a regimen switch to trifluridine and tipiracil hydrochloride was considered, he opted for best supportive care at 4.8 years after the initial surgery. Carcinomatous ascites has been well controlled, and he remains alive 5.4 years after the initial surgery. Time course of this patient (e.g., surgical resections and chemotherapy regimens) was summarized in Figure 7.\n\nDiscussion\nThe primary cancers that are most frequently responsible for pancreatic metastases are reportedly renal cell carcinoma (54.3–83.3%) and rectal cancer (7.5–16.7%) [2,9,12,20]. The median interval between resection of the primary cancer and development of pancreatic metastases is relatively longer, being reportedly 32.5–157 months [5,7–9,20]. Pancreatic metastases appearing long after the initial surgery (>5 years) have been documented [4]. However, T1 colorectal cancers according to TNM classification [19] (i.e., oncological depth within submucosal layer) rarely cause pancreatic metastases [9].\n\nAccurate preoperative diagnosis of pancreatic metastasis rather than a primary pancreatic cancer is difficult [7–10,12]. Cytological examination of a fine needle aspirate or pathological examination of a biopsy specimen obtained under endoscopic ultrasonography guidance is useful for preoperative diagnosis [4,8,9,20,21]. In our case, although pathological assessment of a biopsy specimen suggested moderately-differentiated tubular adenocarcinoma, it was not possible to make a definite preoperative diagnosis of pancreatic metastasis originating from rectal cancer, which was regrettable given the impact the diagnosis made on subsequent management. Unfortunately, the clinical features, particularly the findings on imaging studies (e.g., obstructive jaundice with biliary dilatation and associated pancreatitis with dilated pancreatic duct), misled us into diagnosing primary pancreatic cancer. It must always be kept in mind that a pancreatic metastasis may closely resemble the more common primary pancreatic tumor. Only 1.3% of pancreatic metastases originate from colorectal cancer [7] and the pancreas is a very rare site for metastases from colorectal cancer [3–13]; thus, the statistical unlikelihood of metastasis was a factor in our preoperative misdiagnosis.\n\nThe usefulness of immunohistological staining for cytokeratin 7, cytokeratin 20, and caudal type homeobox transcription factor 2 is well-documented [4,7,9,14]. Negativity for cytokeratin 7 and positivity for cytokeratin 20 favor colorectal cancer over primary pancreatic cancer [7,9]; however, immunohistological assessment is not practicable as an intraoperative diagnostic tool. Although thyroid transcription factor 1 specifically expresses in most thyroid tumors and in a significant subset of pulmonary neoplasms [22], combinations of cytokeratin 7, cytokeratin 20, and caudal type homeobox transcription factor 2 are not specific for colorectal cancer.\n\nOptimal treatment for pancreatic metastasis has not yet been established [5,8,10,15,20]. Pancreatic resection may confer a survival benefit on patients with pancreatic metastases [2,5–10,12–15,20], the 5-year survival rate after this procedure reportedly being approximately 30% [23]. Cases of successfully resected pancreatic metastases from colorectal cancer after multiple resections of metastatic lesions have been reported [2,5–10,12–14,24]. Thus, patients who are fit for surgery and free of metastases in other organs should be considered good candidates for pancreatic resection [2,5–10,12–14,24].\n\nThe role of intentional lymphadenectomy in patients with pancreatic metastases is controversial [10,12,23]; pancreatic metastasis may be accompanied by lymphoid metastases in regional lymph nodes [8,23]. The mortality and morbidity rates for pancreatic resections including pancreaticoduodenectomy for pancreatic metastasis are reportedly 1.4% and 48.3%, respectively [2]. Simple pancreatic resection without intentional dissection of lymph nodes and nerve plexus is currently considered safe and feasible [25]; intentional lymphadenectomy increases the risk of pancreatic leakage [25].\n\nPancreatic cancer is a solid cancer with a poor prognosis [1]; pancreatic metastases also have a poor prognosis (8.7 months) [10]. In the absence of a definitive diagnosis of pancreatic metastasis, it is not possible to select the optimal chemotherapy regimen [13,26]. From the viewpoint of therapeutic strategy, surgical resection of a pancreatic mass is justified not only to make a definitive diagnosis [8,13,26] but also to improve survival [2,5,6,8–10,12–15,20]. The overall survival of patients with stage IV colorectal cancer is approximately 9 months if chemotherapy is not administered after primary resection [17]. Multimodality therapy is crucial for stage IV colorectal cancer [16,17]. As in our case, aggressive treatment aimed at achieving radiographic and/or surgical R0 should be repeatedly administered to patients with colorectal cancer when they develop recurrences and metastases.\n\nConclusions\nMetachronous pancreatic metastasis originating from rectal cancer can masquerade clinically and radiographically as a primary pancreatic cancer. The possibility of a rare, easily misdiagnosed metastatic tumor in the pancreas must always be kept in mind. Aggressive surgery for pancreatic metastases is justified, not only to make a definitive diagnosis to inform selection of subsequent chemotherapy but also to improve survival, even in the presence of recurrences and metastases provided radiographic and/or surgical curative resection can be accomplished.\n\nWe are grateful to Yoshihiro Yamamoto and Masayuki Shintaku (Department of Pathology, Shiga General Hospital, Moriyama, Japan) for their assistance with the histopathological and immunopathological assessments.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Findings on dynamic computed tomography (CT). At 2.5 years after the initial surgery, a diffuse and low-density nodule (yellow arrows) was detected in the pancreatic head. This hypovascular nodule shows no enhancement on dynamic CT. The distal pancreatic duct is dilated and there is evidence of associated pancreatitis.\n\nFigure 2. Findings on endoscopic ultrasonography. The low echoic and diffuse nodule (A) (yellow arrows) was 21×19 mm in size and Doppler ultrasonography (B) revealed that it was hypovascular.\n\nFigure 3. The finding on magnetic resonance imaging. The finding on magnetic resonance cholangiopancreatography is shown. The distal pancreatic duct, intrahepatic bile ducts, and extrahepatic biliary tract are remarkably dilated as a result of obstruction in the pancreatic head.\n\nFigure 4. The finding on endoscopic retrograde cholangiopancreatography and biliary drainage by nasobiliary drainage tube. The finding on endoscopic retrograde cholangiopancreatography is shown (A). The resultant obstructive jaundice was progressive and biliary drainage was required. A nasobiliary drainage tube was placed endoscopically (B).\n\nFigure 5. Histopathological assessment. Pathological findings on hematoxylin-eosin stained sections are shown (100×). The pathological features of the rectal cancer (A) and pancreatic neoplasm (B) are similar.\n\nFigure 6. Immunohistological studies. Pathological finding on hematoxylin-eosin staining (A) and immunohistological findings on cytokeratin 7 (B), cytokeratin 20 (C), and caudal type homeobox transcription factor 2 (D) in the pancreatic tumor were shown (20×).\n\nFigure 7. Time course of this patient. Time course of this patient (e.g., surgical resections and chemotherapy regimens) was summarized.\n==== Refs\nReferences:\n1. Kamisawa T Wood LD Itoi T Takaori K Pancreatic cancer Lancet 2016 388 73 85 26830752 \n2. Huang Q Zhou H Liu C Surgical resection for metastatic tumors in the pancreas: A single-center experience and systematic review Ann Surg Oncol 2019 26 1649 56 30924017 \n3. Greve E Dumas O Fumex F Solitary pancreatic metastasis four years after curative treatment for rectal carcinoma Gastroenterol Clin Biol 2008 32 258 60 18456107 \n4. Sano I Katanuma A Yane K Pancreatic metastasis from rectal cancer that was diagnosed by endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) Intern Med 2017 56 301 5 28154274 \n5. Sperti C Pasquali C Berselli M Metastasis to the pancreas from colorectal cancer: Is there a place for pancreatic resection? Dis Colon Rectum 2009 52 1154 59 19581861 \n6. Hino H Kagawa H Kinugasa Y Long-term survival with surgery for metachronous retroperitoneal lymph node and pancreatic metastases after curative resection of rectal cancer: a case report Surg Case Rep 2016 2 49 27225417 \n7. Yamaguchi T Takii Y Maruyama S [Four cases of resectable metastatic pancreatic cancer from colorectal cancers] The Japanese Journal of Gastroenterological Surgery 2012 45 740 48 [in Japanese] \n8. Okumura S Yoshimura T Fujita K [A case of metachronous metastasis to the pancreas from rectal cancer] Journal of the Japan Pancreas Society 2014 29 253 62 [in Japanese] \n9. Sakon M Hamada J Sekino Y [A case of metachronous metastasis of the pancreas from rectal cancer] Journal of the Japan Pancreas Society 2008 23 748 54 [in Japanese] \n10. Ishigure K Kawase Y Kanazumi N [Report of three resected cases of pancreatic metastatic tumors] The Japanese Journal of Gastroenterological Surgery 2000 33 1686 90 [in Japanses] \n11. Bachmann J Michalski CW Bergmann F Metastasis of rectal adenocarcinoma to the pancreas. Two case reports and a review of the literature JOP 2007 8 214 22 17356246 \n12. Tatsuzawa Y Kurokawa M Mochiki Y [A case of pancreatic metastasis from colorectal cancer] The Japanese Journal of Gastroenterological Surgery 2001 34 132 36 \n13. Lee CW Wu RC Hsu JT Isolated pancreatic metastasis from rectal cancer: A case report and review of literature World J Surg Oncol 2010 8 26 20374636 \n14. Matsubara N Baba H Okamoto A Rectal cancer metastasis to the head of the pancreas treated with pancreaticoduodenectomy J Hepatobiliary Pancreat Surg 2007 14 590 94 18040627 \n15. You DD Choi DW Choi SH Surgical resection of metastasis to the pancreas J Korean Surg Soc 2011 80 278 82 22066048 \n16. Lintoiu-Ursut B Tulin A Constantinoiu S Recurrence after hepatic resection in colorectal cancer liver metastasis – Review article J Med Life 2015 8 12 14 \n17. Japanese Society for Cancer of the Colon and Rectum JSCCR guidelines 2019 for the treatment of colorectal cancer Tokyo Kanehara 2019 \n18. Japanese Society for Cancer of the Colon and Rectum Japanese classification of colorectal, appendiceal and anal carcinoma 9th edition Tokyo Kanehara 2018 \n19. Union for International Cancer Control TNM classification of malignant tumors 8th edition New York Wiley Blackwell 2017 \n20. Endo Y Noda H Watanabe F A retrospective analysis of preoperative evaluation and surgical resection for metastatic tumors of the pancreas Indian J Surg Oncol 2019 10 251 57 31168244 \n21. Hussain T Salamat A Farooq MA Indications for endoscopic ultrasound and diagnosis on fine-needle aspiration and cytology J Coll Physicians Surg Pak 2009 19 223 27 19356336 \n22. Aversa S Bellan C TTF1 expression in pulmonary metastatic rectal adenocarcinoma Case Rep Gastrointest Med 2018 2018 6405125 30631609 \n23. Reddy S Wolfgang CL The role of surgery in the management of isolated metastases to the pancreas Lancet Oncol 2009 10 287 93 19261257 \n24. Saito M Teranishi F Shibata T [A case of resected pancreatic metastasis of rectal cancer after multiple resections of metastatic lesions] Gan To Kagaku Ryoho 2019 46 327 29 [in Japanese] 30914549 \n25. Hori T Yamamoto H Harada H Inferior pancreaticoduodenal artery aneurysm related with groove pancreatitis persistently repeated hemosuccus pancreaticus even after coil embolization Am J Case Rep 2019 20 567 74 31006768 \n26. Yabe N Murai S Ozawa H [A case of unresectable advanced rectal cancer with a pancreatic tumor that was successfully treated with FOLFIRINOX] Gan To Kagaku Ryoho 2016 43 2468 70 28133357\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "20()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000368:Aged; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D012004:Rectal Neoplasms", "nlm_unique_id": "101489566", "other_id": null, "pages": "1781-1787", "pmc": null, "pmid": "31784503", "pubdate": "2019-11-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31168244;18040627;26361505;26830752;27225417;30631609;19356336;17356246;19261257;30924017;30914549;28133357;28154274;18456107;22066048;20374636;19581861;31006768", "title": "Metachronous Pancreatic Metastasis from Rectal Cancer that Masqueraded as a Primary Pancreatic Cancer: A Rare and Difficult-to-Diagnose Metastatic Tumor in the Pancreas.", "title_normalized": "metachronous pancreatic metastasis from rectal cancer that masqueraded as a primary pancreatic cancer a rare and difficult to diagnose metastatic tumor in the pancreas" }

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METACHRONOUS PANCREATIC METASTASIS FROM RECTAL CANCER THAT MASQUERADED AS A PRIMARY PANCREATIC CANCER: A RARE AND DIFFICULT-TO- DIAGNOSE METASTATIC TUMOR IN THE PANCREAS. 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{ "abstract": "Background: Patients with chronic obstructive pulmonary disease have a high prevalence of osteoporosis, and different osteoporosis drugs are used to prevent fractures in these patients. Although the overall incidence of complete or incomplete, atypical femoral fracture (AFF) is low, long-term use of antiresorptive agents is associated with an increased risk of developing AFF. Methods: We present a patient with chronic obstructive pulmonary disease with recurrent symptoms of an incomplete AFF who had been treated with glucocorticoids, and sequentially with alendronate, zoledronic acid, strontium ranelate, raloxifene, denosumab and finally with teriparatide. The first episode occurred before osteoporosis therapies, the second after bisphosphonate treatments, and the third under denosumab. Results: Although her symptoms resolved along with gradually healing of fracture lines after conservative treatment without surgical intervention, progressive varus deformity of the proximal femur may have contributed to recurrence of AFF. Conclusion: Early treatment with anabolic agents and prophylactic fixation of incomplete AFF may alleviate symptoms and prevent recurrences.", "affiliations": "Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopaedic Surgery, National Taiwan University Hospital , Taipei Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.;Department of Orthopedics, En Chu Kong Hospital , New Taipei City , Taiwan.", "authors": "Lai|Kun-Hung|KH|;Chiang|Chih-Yung|CY|;Yang|Rong-Sen|RS|https://orcid.org/0000-0002-0979-4463;Yang|Kai-Chiang|KC|https://orcid.org/0000-0002-0979-4463;Wu|Chang-Chin|CC|https://orcid.org/0000-0002-9309-5824", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005938:Glucocorticoids; D000069448:Denosumab", "country": "England", "delete": false, "doi": "10.1080/17843286.2018.1534576", "fulltext": null, "fulltext_license": null, "issn_linking": "1784-3286", "issue": "74(5)", "journal": "Acta clinica Belgica", "keywords": "Chronic obstructive pulmonary disease; atypical femoral fracture; bisphosphonate; denosumab; glucocorticoid; incomplete", "medline_ta": "Acta Clin Belg", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D000072700:Conservative Treatment; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D017102:Fracture Healing; D005938:Glucocorticoids; D006801:Humans; D010024:Osteoporosis; D029424:Pulmonary Disease, Chronic Obstructive; D012008:Recurrence", "nlm_unique_id": "0370306", "other_id": null, "pages": "370-374", "pmc": null, "pmid": "30336748", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Conservative treatment of recurrent symptoms of an incomplete, atypical femoral fracture associated with glucocorticoid, bisphosphonate, and denosumab therapy in a patient with chronic obstructive pulmonary disease.", "title_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROLIA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI K-H, CHIANG C-Y, YANG R-S, YANG K-C, WU C-C. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLIN BELG. 2019?74 (5):370 374", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20191016", "receivedate": "20191005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16887687, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TW-BAUSCH-BL-2018-031522", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR LONG TIME", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200307" } }, "primarysource": { "literaturereference": "LAI K, CHIANG C, YANG R, WU C. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLINICA BELGICA. INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE. 2018?.", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181116", "receivedate": "20181116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15628032, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "PHHY2018TW156305", "fulfillexpeditecriteria": "1", "occurcountry": "TW", 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"drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERIPARATIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERIPARATIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RALOXIFENE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALOXIFENE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DENOSUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DENOSUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD (FOR LONG TIME)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200307" } }, "primarysource": { "literaturereference": "LAI KH, CHIANG CY, YANG RS, YANG KC, WU CC. CONSERVATIVE TREATMENT OF RECURRENT SYMPTOMS OF AN INCOMPLETE, ATYPICAL FEMORAL FRACTURE ASSOCIATED WITH GLUCOCORTICOID, BISPHOSPHONATE, AND DENOSUMAB THERAPY IN A PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ACTA CLINICA BELGICA: INTERNATIONAL JOURNAL OF CLINICAL AND LABORATORY MEDICINE. 2018", "literaturereference_normalized": "conservative treatment of recurrent symptoms of an incomplete atypical femoral fracture associated with glucocorticoid bisphosphonate and denosumab therapy in a patient with chronic obstructive pulmonary disease", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181120", "receivedate": "20181120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15641310, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "We present a report of what we believe was an extremely rare case of hyperacute respiratory failure caused by first time exposure to cyclophosphamide in a 40-year-old woman with systemic lupus erythematosus. The patient was extensively evaluated for alternative etiologies with negative results. Treatment with methylprednisolone and high doses of human immunoglobulin resulted in gradual improvement of the patient's condition. We review the literature with regard to cyclophosphamide-induced lung toxicity.", "affiliations": "Department of Nephrology, Aalborg University Hospital, Mølleparkvej 4, 9000, Aalborg, Denmark, pschjelderup@gmail.com.", "authors": "Schjelderup|P|P|;El-Galaly|T C|TC|;Frøkjær|J B|JB|;Ring|T|T|", "chemical_list": "D018501:Antirheumatic Agents; D007136:Immunoglobulins; D003520:Cyclophosphamide; D008775:Methylprednisolone", "country": "Germany", "delete": false, "doi": "10.1007/s00393-014-1381-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0340-1855", "issue": "73(10)", "journal": "Zeitschrift fur Rheumatologie", "keywords": null, "medline_ta": "Z Rheumatol", "mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007261:Infusions, Intra-Arterial; D008180:Lupus Erythematosus, Systemic; D008775:Methylprednisolone; D012128:Respiratory Distress Syndrome; D016896:Treatment Outcome", "nlm_unique_id": "0414162", "other_id": null, "pages": "939-41", "pmc": null, "pmid": "24830677", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19786984;9415567;20692540;6809197;12209517;781905;9625032;1068740;8970380", "title": "Acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus.", "title_normalized": "acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus" }

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{ "abstract": "BACKGROUND\nDermatomyositis is an autoimmune disease of unknown etiology characterized by inflammation of the skin and muscles. Several medications have been implicated in the development of dermatomyositis; however, the disease has rarely been linked to the use of tumor necrosis factor (TNF) inhibitors. We report 4 cases of dermatomyositis that developed or were exacerbated by exposure to the TNF inhibitors etanercept and adalimumab. Observation Four patients with symptoms of inflammatory arthritis were treated with TNF inhibitors for a duration ranging from 2 months to 2 years. All 4 patients developed symptoms consistent with dermatomyositis, including inflammatory rash and muscle weakness. Their symptoms persisted after discontinuation of the treatment with the TNF inhibitors but responded to treatment with corticosteroids and immunosuppressive medications.\n\n\nCONCLUSIONS\nTumor necrosis factor inhibitors have been associated with the onset of a number of autoimmune disorders, most commonly vasculitis and a lupuslike syndrome. Rarely have they been associated with dermatomyositis. The 4 cases reported herein indicate that TNF inhibitor use can be associated with either induction or exacerbation of dermatomyositis.", "affiliations": "Department of Medicine, Division of Rheumatology, University of Pennsylvania School of Medicine, Perelman Center for Advanced Medicine, First Floor South Pavilion, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.", "authors": "Klein|Rachel|R|;Rosenbach|Misha|M|;Kim|Ellen J|EJ|;Kim|Brian|B|;Werth|Victoria P|VP|;Dunham|Jonathan|J|", "chemical_list": "D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept", "country": "United States", "delete": false, "doi": "10.1001/archdermatol.2010.142", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-987X", "issue": "146(7)", "journal": "Archives of dermatology", "keywords": null, "medline_ta": "Arch Dermatol", "mesh_terms": "D000328:Adult; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D015551:Autoimmunity; D003882:Dermatomyositis; D003937:Diagnosis, Differential; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0372433", "other_id": null, "pages": "780-4", "pmc": null, "pmid": "20644041", "pubdate": "2010-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10580639;17632266;15158749;18625537;16705109;15899052;17763410;8960740;12796126;17139649;10399751;11055823;19416947;19028367;12506773;16960940;18272672;10579123;15996057;11762947;15297281;15852401;11256887", "title": "Tumor necrosis factor inhibitor-associated dermatomyositis.", "title_normalized": "tumor necrosis factor inhibitor associated dermatomyositis" }

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TUMOR NECROSIS FACTOR INHIBITOR-ASSOCIATED DERMATOMYOSITIS. ARCHIVES OF DERMATOLOGY. 2010?146 (7):780-784", "literaturereference_normalized": "tumor necrosis factor inhibitor associated dermatomyositis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16789138, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-AMGEN-USASP2019145569", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETANERCEPT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETANERCEPT" } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aldolase increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rheumatoid factor increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Antinuclear antibody increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Photosensitivity reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIM ELLEN J.. TUMOR NECROSIS FACTOR INHIBITOR-ASSOCIATED DERMATOMYOSITIS. ARCHIVES OF DERMATOLOGY. 2010?146 (7):780-784", "literaturereference_normalized": "tumor necrosis factor inhibitor associated dermatomyositis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190910", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16789201, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "In this nationwide population-based study, we examined whether haloperidol exposure is associated with a higher risk of mortality than are other antipsychotic medications. Patients who newly received monotherapy with chlorpromazine (n = 2133), haloperidol (n = 4454), quetiapine (n = 1513), and risperidone (n = 1046) between January 1, 2001, and December 31, 2011, were selected from a random sample of the 1 million enrollees of the Taiwan National Health Insurance Research Database. The association between antipsychotic prescription and mortality was estimated through Cox proportional hazard regression. To examine the mortality rates of antipsychotics at different exposure durations, we compared the differences among short-term (≤30 days), midterm (31-90 days), and long-term (>90 days) antipsychotic use. The mortality rates during the follow-up among the chlorpromazine, haloperidol, quetiapine, and risperidone groups were 17.4%, 45.5%, 26.8%, and 25.9%, respectively. The mortality risk among patients receiving haloperidol was the highest within 30 days of the prescription, after which the risk reduced rapidly. Compared with the patients receiving chlorpromazine, the mortality risk was higher in short-term (adjusted hazard ratio, 2.11; 95% confidence interval, 1.87-2.39) and midterm haloperidol users (1.86; 1.54-2.25) than in long-term users (0.99; 0.61-1.61). In conclusion, haloperidol use is associated with higher mortality risk than other antipsychotic medications. The mortality risk varies according to the duration of drug exposure. Underlying characteristics and medical conditions may influence the estimation of the mortality risk. Clinicians should pay attention to the mortality risk when prescribing antipsychotic medications, particularly for the elderly and critically ill patients.", "affiliations": "From the *Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine; †Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; ‡Institute of Statistical Science, Academia Sinica; §Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica; ∥Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei; ¶Community Medicine Research Center, Chang-Gung Memorial Hospital, Keelung, Taiwan; #Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; and **Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.", "authors": "Wang|Liang-Jen|LJ|;Lee|Sheng-Yu|SY|;Yuan|Shin-Sheng|SS|;Yang|Kang-Chung|KC|;Yang|Chun-Ju|CJ|;Lee|Tung-Liang|TL|;Shyu|Yu-Chiau|YC|", "chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D006220:Haloperidol; D018967:Risperidone; D002746:Chlorpromazine", "country": "United States", "delete": false, "doi": "10.1097/JCP.0000000000000451", "fulltext": null, "fulltext_license": null, "issn_linking": "0271-0749", "issue": "36(1)", "journal": "Journal of clinical psychopharmacology", "keywords": null, "medline_ta": "J Clin Psychopharmacol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D002746:Chlorpromazine; D016638:Critical Illness; D005260:Female; D005500:Follow-Up Studies; D006220:Haloperidol; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D016016:Proportional Hazards Models; D000069348:Quetiapine Fumarate; D012189:Retrospective Studies; D012307:Risk Factors; D018967:Risperidone; D013624:Taiwan; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "8109496", "other_id": null, "pages": "9-17", "pmc": null, "pmid": "26658260", "pubdate": "2016-02", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Risk of Mortality Among Patients Treated With Antipsychotic Medications: A Nationwide Population-Based Study in Taiwan.", "title_normalized": "risk of mortality among patients treated with antipsychotic medications a nationwide population based study in taiwan" }

[ { "companynumb": "TW-JNJFOC-20151224672", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "015923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WANG L, LEE S, YUAN S, YANG K, YANG C, LEE T, ET AL. RISK OF MORTALITY AMONG PATIENTS TREATED WITH ANTIPSYCHOTIC MEDICATIONS: A NATIONWIDE POPULATION-BASED STUDY IN TAIWAN. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 2016?36(1):9-17.", "literaturereference_normalized": "risk of mortality among patients treated with antipsychotic medications a nationwide population based study in taiwan", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20151231", "receivedate": "20151231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11883201, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky.\n\n\n\nWe describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits.\n\n\n\nThe evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.", "affiliations": "Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Department of Neurology, Boston Children's Hospital, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.", "authors": "Lehman|Laura L|LL|;Bruccoleri|Rebecca|R|;Danehy|Amy|A|;Swanson|Julie|J|;Mrakotsky|Christine|C|;Smith|Edward|E|;Orbach|Darren B|DB|;Burstein|Rami|R|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0333102420950484", "fulltext": null, "fulltext_license": null, "issn_linking": "0333-1024", "issue": "41(1)", "journal": "Cephalalgia : an international journal of headache", "keywords": "CGRP receptor monoclonal antibody; Cerebral proliferative angiopathy; headache; migraine", "medline_ta": "Cephalalgia", "mesh_terms": null, "nlm_unique_id": "8200710", "other_id": null, "pages": "122-126", "pmc": null, "pmid": "32814432", "pubdate": "2021-01", "publication_types": "D016422:Letter", "references": null, "title": "Adverse effects of erenumab on cerebral proliferative angiopathy: A case report.", "title_normalized": "adverse effects of erenumab on cerebral proliferative angiopathy a case report" }

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{ "abstract": "Spontaneous hypoglycemia is a puzzling clinical problem and an important reason for referral to endocrinologists. Several clinical conditions such as insulinomas, non-insulinoma pancreatogenous hypoglycemia syndrome, insulin autoimmune syndrome, postprandial hypoglycemia (reactive hypoglycemia), non-islet cell tumor hypoglycemia, primary adrenal insufficiency, hypopituitarism, and critical illness can be associated with spontaneous hypoglycemia. Rarely, in patients with mental health issues, factious hypoglycemia from extrinsic insulin use or ingestion of oral hypoglycemic agents can obfuscate the clinical picture for clinicians trying to identify an organic cause. In those presenting with Whipple's triad (symptoms ± signs of hypoglycemia, low plasma glucose, and resolution symptoms ± signs after hypoglycemia correction), a 72-h supervised fast test with measurement of plasma insulin, c-peptide, pro-insulin, and beta-hydroxybutyrate levels, coupled with plasma/urine sulphonylurea screen, forms the first step in diagnostic evaluation. A mixed meal test is preferable for those with predominantly postprandial symptoms. Additional non-invasive and/or invasive diagnostic evaluation is necessary if an organic hypoglycemic disorder is suspected. With the aid of a few brief clinical case scenarios, we discuss the diagnostic evaluation and management of spontaneous hypoglycemia through this comprehensive article.", "affiliations": "Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK.;Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK.;Department of Endocrinology & Diabetes, New Cross Hospital, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, WV10 0QP, UK. drpappachan@yahoo.co.in.", "authors": "Kandaswamy|Leelavathy|L|;Raghavan|Rajeev|R|;Pappachan|Joseph M|JM|http://orcid.org/0000-0003-0886-5255", "chemical_list": "D001786:Blood Glucose; D007328:Insulin", "country": "United States", "delete": false, "doi": "10.1007/s12020-016-0902-0", "fulltext": null, "fulltext_license": null, "issn_linking": "1355-008X", "issue": "53(1)", "journal": "Endocrine", "keywords": "72-Hour supervised fast test; Insulin autoimmune syndrome; Insulinoma; Non-insulinoma pancreatogenous hypoglycemia syndrome; Non-islet cell tumor hypoglycemia; Postprandial hypoglycemia (reactive hypoglycemia); Spontaneous hypoglycemia", "medline_ta": "Endocrine", "mesh_terms": "D000328:Adult; D001786:Blood Glucose; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007328:Insulin; D007340:Insulinoma; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D019518:Postprandial Period", "nlm_unique_id": "9434444", "other_id": null, "pages": "47-57", "pmc": null, "pmid": "26951054", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25922806;19440117;22188732;25918682;26001537;21470994;23671155;25915566;26760044;23249786;18931647;15767809;21245985;19129539;23074233;26566426;26577133;17127144;24641805;24645840;10190379;24765253;21134557;24423303;21366479;15754739;9356020;10999812;21306234;25002326;26508374;25737101;26312578;23979685;17856569;23636530;26315093;24921202;23430217;16670629;20628679;17609300;17611903;10500933;17609405;26107678;19141587;26050581;7716548;24275188;24622317;24599222;23425640;26704781;24459236;23669476;23082777;22261919;15880279;16253899;10500928;16860583;19088155", "title": "Spontaneous hypoglycemia: diagnostic evaluation and management.", "title_normalized": "spontaneous hypoglycemia diagnostic evaluation and management" }

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{ "abstract": "To evaluate and compare the effectiveness and adverse effects of intramuscular (IM) olanzapine and IM aripiprazole for the treatment of agitated patients with schizophrenia in clinical practice.\n\n\n\nA 24-hour randomized double-blind study carried out at a psychiatric hospital in Thailand enrolled adult patients (18-65years old) with schizophrenia experiencing agitation. Patients received one dose of IM olanzapine or IM aripiprazole followed by routine oral psychotropic medications. Efficacy was primarily measured using the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC).\n\n\n\nA total of 80 patients with a PANSS-EC score range of 22-35 entered the study, of whom 13% had a medical comorbidity and 40% a history of active substance abuse. The 40 patients receiving IM olanzapine showed greater improvement than the 40 patients receiving IM aripiprazole in PANSS-EC scores at 2h after the injection (p=0.002) but not at 24h. The two treatments were well tolerated. Patients receiving IM olanzapine experienced greater somnolence than those receiving IM aripiprazole. There were no clinically relevant changes in vital signs in either group.\n\n\n\nThe results indicate that IM olanzapine and aripiprazole are similarly effective and well tolerated in the real-world treatment of agitation associated with schizophrenia over the first 24h. However, in the early hours, IM olanzapine may produce more sedation and reductions in agitation.", "affiliations": "Nakhon Sawan Rajanagarindra Psychiatric Hospital, Phayuhakhiri, Nakhon Sawan 60130, Thailand. Electronic address: kittipeerachon@outlook.com.;Nakhon Sawan Rajanagarindra Psychiatric Hospital, Phayuhakhiri, Nakhon Sawan 60130, Thailand. Electronic address: warawat@hotmail.co.th.", "authors": "Kittipeerachon|Mantana|M|;Chaichan|Warawat|W|", "chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000068180:Aripiprazole; D000077152:Olanzapine", "country": "Netherlands", "delete": false, "doi": "10.1016/j.schres.2016.07.017", "fulltext": null, "fulltext_license": null, "issn_linking": "0920-9964", "issue": "176(2-3)", "journal": "Schizophrenia research", "keywords": "Agitation; Aripiprazole; Intramuscular; Olanzapine; Schizophrenia", "medline_ta": "Schizophr Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001569:Benzodiazepines; D057186:Comparative Effectiveness Research; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011569:Psychiatric Status Rating Scales; D011595:Psychomotor Agitation; D012559:Schizophrenia; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8804207", "other_id": null, "pages": "231-238", "pmc": null, "pmid": "27461399", "pubdate": "2016-10", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D065007:Pragmatic Clinical Trial", "references": null, "title": "Intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia: A pragmatic double-blind randomized trial.", "title_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial" }

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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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"drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861467, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19412", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONFUSIONAL STATE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861377, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19405", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, OVER A 2-WEEK PERIOD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENTAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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"drugtreatmentdurationunit": null, "medicinalproduct": "LEVOPROMAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORPROMAZINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CASTOR OIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASTOR OIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arteriosclerosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865297, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19408", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENICILLIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOXYMETHYLPENICILLIN BENZATHINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORPROMAZINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861448, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19384", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPENTIXOL DECANOATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPENTHIXOL DECANOATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asphyxia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865298, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19402", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, OVER 6 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861428, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19394", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, IN THE EVENING", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861446, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19381", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMISULPRIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMISULPRIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FERROUS FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS FUMARATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "10 MG, SINGLE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOTEPINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOTEPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic aneurysm rupture", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861129, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19392", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhagic stroke", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865299, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19411", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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SCHIZOPHRENIA RESEARCH.. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856422, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19399", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. 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{ "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AT LEAST 10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetes insipidus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861425, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19383", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BIPERIDEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, SUSTAINED RELEASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BIPERIDEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, 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"summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861215, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19414", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG, UNK, OVER 36 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "AGITATED DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sudden cardiac death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231-238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "1", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865295, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19391", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861475, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19397", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DELUSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19422", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENZTROPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90294", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENZTROPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG, OVER 21 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPHENAZINE DECANOATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPHENAZINE DECANOATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arteriosclerosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856423, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19396", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MANIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYAMEMAZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYAMEMAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOXAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOXAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLORAZEPATE DIPOTASSIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLORAZEPATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161019", "receivedate": "20161019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12861453, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19409", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEPOT ZUCLOPENTHIXOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL. SCHIZOPHRENIA RESEARCH. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161018", "receivedate": "20161018", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12856413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19416", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VITAMIN B" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN B" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, OVER 12 HRS", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENTAL DISORDER DUE TO A GENERAL MEDICAL CONDITION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiopulmonary failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITTIPEERACHON M, CHAICHAN W.. INTRAMUSCULAR OLANZAPINE VERSUS INTRAMUSCULAR ARIPIPRAZOLE FOR THE TREATMENT OF AGITATION IN PATIENTS WITH SCHIZOPHRENIA: A PRAGMATIC DOUBLE-BLIND RANDOMIZED TRIAL.. SCHIZOPHRENIA RESEARCH.. 2016;176:231 TO 238", "literaturereference_normalized": "intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia a pragmatic double blind randomized trial", "qualification": "3", "reportercountry": "TH" }, "primarysourcecountry": "US", "receiptdate": "20161020", "receivedate": "20161020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12865303, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "This review focuses on the evidence for the efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with all stages of chronic kidney disease (CKD) and at all ages. It describes the improving height prognosis for our patients both with and without rhGH; explains the underlying hormonal abnormalities that provide the rationale for rhGH use in CKD and the endocrine changes that accompany treatment; and views on who warrants treatment, with what dose, and how long for.", "affiliations": "Gt Ormond St Hospital for Children NHS Foundation Trust, London, WC1N3JH, UK. lesley.rees@gosh.nhs.uk.", "authors": "Rees|Lesley|L|", "chemical_list": "D011994:Recombinant Proteins; D019382:Human Growth Hormone; D013006:Growth Hormone", "country": "Germany", "delete": false, "doi": "10.1007/s00467-015-3179-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0931-041X", "issue": "31(9)", "journal": "Pediatric nephrology (Berlin, Germany)", "keywords": "Final height; Growth; Growth hormone", "medline_ta": "Pediatr Nephrol", "mesh_terms": "D001827:Body Height; D002648:Child; D006130:Growth Disorders; D013006:Growth Hormone; D019382:Human Growth Hormone; D006801:Humans; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic", "nlm_unique_id": "8708728", "other_id": null, "pages": "1421-35", "pmc": null, "pmid": "26369925", "pubdate": "2016-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": "21398350;15692833;22187956;15682317;19500600;10201017;18584215;19863876;21947116;10912546;22278170;8660044;25659076;12000468;20526632;1715501;9438660;9475286;19965538;22336787;11149116;10912542;7910322;8771007;3352160;8969731;25594438;2587121;15782308;23559676;16583244;8648920;12750982;24178977;3060022;15253735;11149115;12110034;24728472;2769495;20522533;24970873;8120705;7577409;22021715;19159957;16773402;22145447;3133989;10912545;10210991;9773791;23708760;19940493;2319402;2400222;9186890;3117236;9100565;10084780;12376812;9745864;23628375;10872186;24609826;16861941;18198222;3153055;12734746;20013293;2377395;12014516;10775075;9055918;15504147;7525628;1919888;23793884;11006368;7577408;22886280;23582048;24662177;23465957;8792393", "title": "Growth hormone therapy in children with CKD after more than two decades of practice.", "title_normalized": "growth hormone therapy in children with ckd after more than two decades of practice" }

[ { "companynumb": "GB-EMD SERONO-8045318", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589972, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "GB-EMD SERONO-8045319", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "GB-EMD SERONO-8045316", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC KIDNEY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RECOMBINANT HUMAN GROWTH HORMONE (RHGH)" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Benign intracranial hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REES L. GROWTH HORMONE THERAPY IN CHILDREN WITH CKD AFTER MORE THAN TWO DECADES OF PRACTICE. PEDIATRIC NEPHROLOGY (BERLIN, GERMANY). 2015 SEP 14?.", "literaturereference_normalized": "growth hormone therapy in children with ckd after more than two decades of practice", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151002", "receivedate": "20151002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11589973, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "When skin abnormalities in patients extend over several dermatomes, disseminated herpes zoster should be suspected. This complication is most often seen in immunocompromised patients.\n\n\n\nAn 87-year-old patient came to the dermatology outpatient clinic with several vesicles scattered over her body. She was being treated with methotrexate for rheumatoid arthritis. Upon physical examination, we found groups of vesicles in the area of the maxillary nerve as well as several solitary vesicles scattered over her body. We made the diagnosis of 'disseminated herpes zoster'. PCR test of fluid from one of the vesicles found Varicella zoster virus. We treated the patient with intravenous acyclovir for 48 hours after which we treated her with oral acyclovir for another 8 days. We temporarily halted methotrexate. Outpatient follow-up found that the patient's skin abnormalities had diminished significantly.\n\n\n\nThe risk of disseminated herpes zoster depends on several factors. Use of immunosuppressants is often not the only contributing factor. Risk of disseminated herpes zoster in a patient who is being treated with methotrexate depends on age, comorbidities and co-medication of the patient.", "affiliations": "Franciscus Gasthuis en Vlietland,afd. Dermatologie, Rotterdam.;Franciscus Gasthuis en Vlietland,afd. Dermatologie, Rotterdam.;Franciscus Gasthuis en Vlietland,afd. Reumatologie, Rotterdam.", "authors": "Wanders|Sarah L|SL|;Loots|Miriam A M|MAM|;Baak|Mieke|M|", "chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir; D008727:Methotrexate", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2162", "issue": "164()", "journal": "Nederlands tijdschrift voor geneeskunde", "keywords": null, "medline_ta": "Ned Tijdschr Geneeskd", "mesh_terms": "D000212:Acyclovir; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008727:Methotrexate; D012307:Risk Factors", "nlm_unique_id": "0400770", "other_id": null, "pages": null, "pmc": null, "pmid": "33201634", "pubdate": "2020-09-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Risk factors for disseminated herpes zoster.", "title_normalized": "risk factors for disseminated herpes zoster" }

[ { "companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-275566", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated varicella zoster virus infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANDERS SL, LOOTS MAM, BAAK M. RISK FACTORS FOR DISSEMINATED HERPES ZOSTER. NED?TIJDSCHR?GENEESKD. 2020?164(39):A7", "literaturereference_normalized": "risk factors for disseminated herpes zoster", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210719", "receivedate": "20210115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18746097, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "NL-TEVA-2021-NL-1869514", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "058", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "77655", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3000 MILLIGRAM DAILY; THREE TIMES PER DAY BY MOUTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "HERPES ZOSTER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM DAILY; BY MOUTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBDURAL HAEMATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "EYE OINTMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "HERPES ZOSTER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR." } ], "patientagegroup": "6", "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Keratitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANDERS SL, LOOTS MAM, BAAK M. RISK FACTORS FOR DISSEMINATED HERPES ZOSTER. NED?TIJDSCHR?GENEESKD 2020?164(39):A7.", "literaturereference_normalized": "risk factors for disseminated herpes zoster", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210219", "receivedate": "20210121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18769755, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]

{ "abstract": "Concomitant use of anticoagulant and antiplatelet agents can increase the risk of gastrointestinal bleed (GIB). Use of proton pump inhibitors (PPIs) has been proposed to decrease the risk of GIB in patients on combined antithrombotic therapy (CAT).\n\n\n\nTo describe the current utilization of PPIs in veteran patients on CAT and associated clinical predictors of GIB.\n\n\n\nThis retrospective study included patients on CAT receiving PPIs, with at least one of the CAT agents initiated between January 1, 2018 and October 30, 2018. Data were extracted from the computerized patient record system. Primary end point included estimating proportion of patients on CAT receiving PPI co-therapy, describing patient characteristics, and identifying clinical predictors of GIB. Secondary outcomes included reporting GIB events and all-cause mortality. Additional outcome was to validate the five-factor risk score (FFRS) for GIB in patients on CAT and compare its overall predictive performance to HAS-BLED score.\n\n\n\nThis study reports an overall rate of PPI co-therapy in patients on CAT of 40.9% (484/1181), with only 22.3% of patients on CAT receiving PPI for GIB prophylaxis. There was no difference in the mean follow up duration of PPI users and PPI co-therapy (264.01 vs 271.92 days; p=0.3761). Current alcohol use (p=0.005), current smokers (p=0.022), chronic kidney disease (p=0.004), peptic ulcer disease (p<0.001), and non-steroidal anti-inflammatory drug use (p=0.048) were significant predictors of GIB in multivariate analyses of our study cohort. We further provide exploratory validation that use of a simplified FFRS to predict GIB showed a trend towards better overall predictive performance as compared to HAS-BLED score (C-statistic: 0.738; 95% CI 0.684-0.787 for FFRS vs C-statistic: 0.596; 95% CI 0.538-0.653 for HAS-BLED; p=0.0094).\n\n\n\nThis study reports lower rate of PPI co-therapy in veteran patients on CAT per currently available guidance. Further we explore utilization of simplified FFRS model to predict GIB in patients on CAT with long-term PPI co-therapy.", "affiliations": "Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.;Veterans Health Administration - Pharmacy, Salem, Virginia, USA.", "authors": "Patil|Tanvi|T|0000-0001-7257-3463;Murphy|Kimberly|K|;Woodard|Laura|L|;Lebrecht|Morgan|M|", "chemical_list": "D005343:Fibrinolytic Agents; D054328:Proton Pump Inhibitors", "country": "United States", "delete": false, "doi": "10.1002/phar.2477", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0008", "issue": "40(12)", "journal": "Pharmacotherapy", "keywords": "Anticoagulation; Antiplatelets; HAS-BLED; antithrombotic; bleeding risk scores; gastrointestinal bleed; proton pump inhibitor", "medline_ta": "Pharmacotherapy", "mesh_terms": "D000368:Aged; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D054328:Proton Pump Inhibitors; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D014728:Veterans", "nlm_unique_id": "8111305", "other_id": null, "pages": "1219-1227", "pmc": null, "pmid": "33073362", "pubdate": "2020-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Proton Pump Inhibitor Utilization in Veteran Patients on Combined Antithrombotic Therapy and Validation of Simplified Bleeding Risk Score.", "title_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score" }

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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210134, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295476", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186534, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130385", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200454, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130356", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181444, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130380", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200434, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295448", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232724, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130383", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191524, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295470", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "85", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232454, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295495", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232704, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130352", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191377, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295434", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210277, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130355", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181447, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130391", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295431", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232017, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295459", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232437, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210098, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295477", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232438, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130363", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184658, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295494", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232448, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295469", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130389", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184728, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130362", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19196908, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907201", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210116, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130377", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295460", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232436, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130379", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210517", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191466, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130360", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184586, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295426", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232626, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295428", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE MAGNESIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200882", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295461", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232726, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295492", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295489", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295483", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210259, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295419", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200794", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232439, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130378", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130351", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": "6", "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181122, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295452", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907213", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210262, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130373", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186652, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130376", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19196612, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130384", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191522, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295497", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232702, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295450", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130359", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19184590, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1907188", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210726", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210260, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295417", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200794", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL DISORDER PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232440, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130387", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191650, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295465", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232720, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130369", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19197070, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295486", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232700, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295427", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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"drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232625, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130390", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PRASUGREL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRASUGREL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295424", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232015, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295500", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232775, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130388", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19200425, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295421", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIVERTICULUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232435, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130358", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PEPTIC ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210426", "receivedate": "20210426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19181541, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295472", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY 2020?40(12):1219?1227.", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210504", "receivedate": "20210504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19210261, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295453", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295462", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232721, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BAYER-2021-130366", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": "6", "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19186653, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295464", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG,UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232783, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295481", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. 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PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:12:1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19191973, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295498", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "81 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PATIL T, MURPHY K, WOODARD L, LEBRECHT M. PROTON PUMP INHIBITOR UTILIZATION IN VETERAN PATIENTS ON COMBINED ANTITHROMBOTIC THERAPY AND VALIDATION OF SIMPLIFIED BLEEDING RISK SCORE. PHARMACOTHERAPY. 2020?40:(12):1219?1227", "literaturereference_normalized": "proton pump inhibitor utilization in veteran patients on combined antithrombotic therapy and validation of simplified bleeding risk score", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210507", "receivedate": "20210507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19232703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nMutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0-61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias.\n\n\nCONCLUSIONS\nVariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing \"ankyrin-B\" syndrome. (Circ J 2016; 80: 2435-2442).", "affiliations": "Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science.", "authors": "Ichikawa|Mari|M|;Aiba|Takeshi|T|;Ohno|Seiko|S|;Shigemizu|Daichi|D|;Ozawa|Junichi|J|;Sonoda|Keiko|K|;Fukuyama|Megumi|M|;Itoh|Hideki|H|;Miyamoto|Yoshihiro|Y|;Tsunoda|Tatsuhiko|T|;Makiyama|Takeru|T|;Tanaka|Toshihiro|T|;Shimizu|Wataru|W|;Horie|Minoru|M|", "chemical_list": "C498994:ANK2 protein, human; D017487:Ankyrins", "country": "Japan", "delete": false, "doi": "10.1253/circj.CJ-16-0486", "fulltext": null, "fulltext_license": null, "issn_linking": "1346-9843", "issue": "80(12)", "journal": "Circulation journal : official journal of the Japanese Circulation Society", "keywords": null, "medline_ta": "Circ J", "mesh_terms": "D000328:Adult; D017487:Ankyrins; D001145:Arrhythmias, Cardiac; D044466:Asians; D002648:Child; D005091:Exons; D005260:Female; D030342:Genetic Diseases, Inborn; D006801:Humans; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D013577:Syndrome", "nlm_unique_id": "101137683", "other_id": null, "pages": "2435-2442", "pmc": null, "pmid": "27784853", "pubdate": "2016-11-25", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes.", "title_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes" }

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PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRCULATION JOURNAL. 2016;80(12):2435-2442", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170512", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13089294, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "JP-ACS-000498", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLAZOLINE HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLAZOLINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K ET AL. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. 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PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRCULATION JOURNAL . 2016;80(12) : 2435-2442", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170110", "receivedate": "20170110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13100917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-SA-2017SA005776", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201739", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K, ET AL. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRC J. 2016 DEC;80: 2435-42. DOI: 10.1253/CIRCJ.CJ-16-0486. ACCESSED: 2016 OCT 25.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170119", "receivedate": "20170119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13131947, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-BAUSCH-BL-2017-000224", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FAMOTIDINE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "019462", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAMOTIDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETIZOLAM" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETIZOLAM" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Long QT syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES. CIRCULATION JOURNAL. 2016;80(12):2435-2442.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": null, "receiptdate": "20170109", "receivedate": "20170109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13099409, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-ROCHE-1875263", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "63239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "63239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLAZOLINE HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLAZOLINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Torsade de pointes", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Long QT syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "ICHIKAWA M, AIBA T, OHNO S, SHIGEMIZU D, OZAWA J, SONODA K ET AL. PHENOTYPIC VARIABILITY OF ANK2 MUTATIONS IN PATIENTS WITH INHERITED PRIMARY ARRHYTHMIA SYNDROMES.. CIRCULATION JOURNAL. 2016;80(12):2435-2442.", "literaturereference_normalized": "phenotypic variability of ank2 mutations in patients with inherited primary arrhythmia syndromes", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13090790, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "An elderly patient with multiple myeloma (MM) was being treated with several regimens and developed a severe drug eruption, necessitating the use of atovaquone instead of trimethoprim-sulfamethoxazole for pneumocystis pneumonia (PCP) prophylaxis. For progressive MM, treatment with isatuximab, an anti-CD38 monoclonal antibody, was started. During the treatment, he developed Listeria monocytogenes bacteremia and recovered quickly with ampicillin administration. CD38 is closely related to the innate immune response against L. monocytogenes, and isatuximab may increase the risk of infection. Therefore, trimethoprim-sulfamethoxazole may be useful in the prevention of not only PCP but also L. monocytogenes infection.", "affiliations": "Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.;Department of Hematology, Kitakyushu Municipal Medical Center, Japan.", "authors": "Ueno|Toshiyuki|T|;Ohta|Takanori|T|;Imanaga|Hiroshi|H|;Nakazawa|Megumi|M|;Sato|Yoriko|Y|;Sugio|Yasuhiro|Y|;Uchida|Yujiro|Y|;Ohno|Yuju|Y|;Uehara|Yasufumi|Y|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000599209:isatuximab", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.7509-21", "fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34024861\n10.2169/internalmedicine.7509-21\nCase Report\nListeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma\nUeno Toshiyuki 1\nOhta Takanori 1\nImanaga Hiroshi 2\nNakazawa Megumi 3\nSato Yoriko 3\nSugio Yasuhiro 1\nUchida Yujiro 3\nOhno Yuju 1\nUehara Yasufumi 1\n1 Department of Hematology, Kitakyushu Municipal Medical Center, Japan\n2 Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Japan\n3 Department of Infectious Diseases, Kitakyushu Municipal Medical Center, Japan\nCorrespondence to Dr.　Toshiyuki Ueno, toshi.u.57@gmail.com\n\n22 5 2021\n15 11 2021\n60 22 36053608\n8 3 2021\n30 3 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nAn elderly patient with multiple myeloma (MM) was being treated with several regimens and developed a severe drug eruption, necessitating the use of atovaquone instead of trimethoprim-sulfamethoxazole for pneumocystis pneumonia (PCP) prophylaxis. For progressive MM, treatment with isatuximab, an anti-CD38 monoclonal antibody, was started. During the treatment, he developed Listeria monocytogenes bacteremia and recovered quickly with ampicillin administration. CD38 is closely related to the innate immune response against L. monocytogenes, and isatuximab may increase the risk of infection. Therefore, trimethoprim-sulfamethoxazole may be useful in the prevention of not only PCP but also L. monocytogenes infection.\n\nListeria monocytogenes\nCD38\nisatuximab\nmultiple myeloma\n==== Body\npmcIntroduction\n\nListeria monocytogenes is a Gram-positive bacterium that enters the human body orally through food, such as meat and dairy products. Although L. monocytogenes is rarely pathogenic to humans, it can cause listeriosis, leading to meningitis and bacteremia in pregnant women, infants, elderly individuals, and cancer patients, with a high mortality rate (1,2).\n\nInvasive listeriosis sometimes develops in patients with hematologic malignancies, especially in those who have undergone stem cell transplantation because of severe insufficiency of cell-mediated immunity (3). In recent years, new agents with different mechanisms of action have been developed for the treatment of various hematologic malignancies. These agents can cause complex changes in immunity.\n\nIsatuximab, a monoclonal antibody that binds a specific epitope on the human CD38 receptor, is highly effective against multiple myeloma (MM). CD38 is closely related to the regulation of innate immunity against L. monocytogenes infection (4). Therefore, the use of isatuximab may be associated with an increase in the rate of Listeria infections.\n\nWe herein report a patient with MM who developed L. monocytogenes bacteremia during isatuximab therapy.\n\nCase Report\n\nThe patient, a 68-year-old Japanese man, presented with initial complaints of back pain. He was diagnosed with IgG lambda-type, symptomatic MM and thereafter received treatment at our institution for three years. At the time of the diagnosis, the patient's serum IgG level was 6,458 mg/dL, while the levels of serum-free lambda and kappa light chains were 970 and 13.7 mg/L, respectively. Bone marrow aspiration showed hyperplastic bone marrow with 48% abnormal plasma cells. A chromosome test revealed deletion of the Y chromosome but no other high-risk chromosomal abnormalities. Based on the revised international staging system for MM, the case was categorized as stage III.\n\nThe patient was treated with bortezomib, lenalidomide, and dexamethasone (VRD) as first-line therapy. Trimethoprim-sulfamethoxazole (TMP-SMX) was also started at the beginning of the treatment to prevent pneumocystis pneumonia (PCP). After two cycles of VRD, the patient achieved a partial response and was subsequently treated with lenalidomide and dexamethasone (RD) therapy. During RD therapy, the patient developed a severe skin rash suspected of being drug eruption; treatment for MM was therefore discontinued, and corticosteroids were started. Since the drug-induced lymphocyte stimulation test (DLST) was positive for several drugs, including TMP-SMX, the suspected drugs were discontinued, and PCP prophylaxis was substituted with aerosolized pentamidine.\n\nThe patient's MM worsened with mass formation in the sternum and clavicle. Therefore, the patient was subjected to several treatment modalities to address the relapse. Carfilzomib, lenalidomide, and dexamethasone (KRD) therapy was first administered, followed by daratumumab, bortezomib, and dexamethasone (DVD) and then pomalidomide and dexamethasone (PD) therapy. Following that, ixazomib, lenalidomide, and dexamethasone (IRD) therapy was concurrently administered with radiation, which was followed by PD therapy. The patient was subsequently treated with elotuzumab, pomalidomide, and dexamethasone (EPD) therapy. However, despite receiving the above-mentioned treatments, his MM progressively worsened. Therefore, isatuximab, pomalidomide, and dexamethasone (Isa-PD) therapy was started. At this time, atovaquone was being used for PCP prophylaxis.\n\nThe Isa-PD schedule was planned with isatuximab 10 mg/kg on days 1, 8, 15, and 22; pomalidomide 2 mg (maximum tolerated dose) on days 1 to 21; and dexamethasone 40 mg on days 1, 8, 15, and 22. Atovaquone was used for PCP prophylaxis, and a small dose of a corticosteroid was continued to treat the drug eruption. On day 5 after the onset of Isa-PD therapy, the patient developed a high fever and hypotension and was administered cefepime under suspicion of febrile neutropenia (FN).\n\nThe laboratory test data collected at that time are summarized in Table. Blood culture samples were positive for a Gram-positive bacterium, which was confirmed to be L. monocytogenes. The isolate was found to be sensitive to ampicillin (minimum inhibitory concentration of 0.5 μg/mL). The patient had no gastrointestinal symptoms prior to the development of L. monocytogenes bacteremia and no symptoms or signs suggestive of meningitis or encephalitis. Treatment was then switched from cefepime to ampicillin for 14 days, and his symptoms resolved rapidly with ampicillin treatment. Furthermore, MM showed a good response despite the interruption of Isa-PD treatment after day 21. Whether or not TMP-SMX treatment was the main cause of the drug eruption was unclear, since the DLST was positive for several drugs, and the skin rash was clearly improved at the time. Therefore, TMP-SMX was resumed in small doses on a trial basis during the second cycle of Isa-PD therapy, and neither the skin rash nor L. monocytogenes bacteremia relapsed.\n\nTable. Laboratory Findings at the Onset of Bacteremia.\n\nComplete blood cell count\tBlood chemistry\t\t\t\t\nWhite blood cell\t10,200\t/µL\tTotal protein\t6.7\tg/dL\tBlood urea nitrogen\t49.8\tmg/dL\t\nNeutrophil\t94.9\t%\tAlbumin\t1.9\tg/dL\tCreatinine\t1.4\tmg/dL\t\nLymphocyte\t1.2\t%\tTotal bilirubin\t0.6\tmg/dL\tCreatine kinase\t14\tU/L\t\nMonocyte\t3.3\t%\tAspartate transaminase\t32\tU/L\tAmylase\t125\tU/L\t\nEosinophil\t0.2\t%\tAlanine aminotransferase\t35\tU/L\tUric acid\t6.4\tmg/dL\t\nBasophil\t0.4\t%\tLactate dehydrogenase\t128\tU/L\tC-reactive protein\t7.35\tmg/dL\t\nHemoglobin\t9.3\tg/dL\tAlkaline phosphatase\t222\tU/L\t\t\t\t\nPlatelet\t20.8×104\t/µL\tγ-Glutamyltransferase\t91\tU/L\t\t\t\t\n\nFigure shows the complete treatment regimen of the patient after MM was diagnosed.\n\nFigure. Clinical course of the patient. DVD: daratumumab, lenalidomide, and dexamethasone, EPD: elotuzumab, pomalidomide, and dexamethasone, IRD: ixazomib, lenalidomide, and dexamethasone, Isa-PD: isatuximab, pomalidomide, and dexamethasone, KRD: carfilzomib, lenalidomide, and dexamethasone, LM: Listeria monocytogenes, MM: multiple myeloma, PCP: pneumocystis pneumonia, PD: pomalidomide and dexamethasone, RD: lenalidomide and dexamethasone, TMP-SMX: trimethoprim-sulfamethoxazole, VRD: bortezomib, lenalidomide, and dexamethasone\n\nDiscussion\n\nL. monocytogenes is an intracellular parasitic bacterium that can survive and proliferate within macrophages. Cell-mediated immunity by immune cells, such as activated macrophages and dendritic cells, plays an important role in the innate immune response against L. monocytogenes (5). CD38 is expressed in activated macrophages and is essential for their regulation. It has been shown that CD38-knockout mice have increased susceptibility to L. monocytogenes infection due to the inhibition of macrophage migration to the infection site (4). This may also be observed in humans, since CD38 is also induced in human macrophages upon infection (6). Therefore, monoclonal antibodies, such as daratumumab, which targets CD38, also highly expressed in myeloma cells, may increase the risk of L. monocytogenes infection. In a nested case-control study conducted on patients amid an outbreak at a commercial eatery, patients who received daratumumab were at a 340-fold higher risk of developing L. monocytogenes infection than other cancer patients. In addition, patients treated with daratumumab had a 75-fold higher risk of listeriosis than all other MM patients, although the study included high-risk patients who underwent stem cell transplantation and received experimental therapies for relapsed refractory disease (7). In fact, there have been two case reports of L. monocytogenes infections after the administration of daratumumab (8,9). Isatuximab is a human anti-CD38 monoclonal antibody similar to daratumumab; however, the antibody targets different amino acid sequences and possesses strong proapoptotic activity independent of cross-linking agents (10). As demonstrated in this case, isatuximab may be a risk factor for the development of L. monocytogenes infection, similar to daratumumab.\n\nThe other risk factors that may lead to L. monocytogenes infection include pregnancy, organ transplant, tumor necrosis factor antagonists, cancer chemotherapy, old age, diabetes, and high-dose steroids (1,2). Therefore, the L. monocytogenes infection in our patient may not have been due to isatuximab alone but rather to multiple factors, such as MM therapy, old age, and long-term use of corticosteroids. However, throughout the course of treatment in this case, which included daratumumab therapy as well, L. monocytogenes infection did not develop. The infection first developed after the administration of isatuximab, suggesting that isatuximab was an important factor in the establishment of the infection.\n\nRoutine stool culture is not recommended for L. monocytogenes detection, as asymptomatic fecal carriage complicates the prediction of the risk of infection (2). This difficulty in reliably predicting conditions that cause L. monocytogenes infection can result in severe infections in patients with hematologic malignancies when the bacterium becomes pathogenic (3). Therefore, prevention and early treatment of L. monocytogenes infection are important. The primary way of preventing L. monocytogenes infection is to avoid consuming contaminated foods, such as dairy products and meat. Second, TMP-SMX, which has been reported as an independent protective factor against L. monocytogenes infection, should be used prophylactically as part of the treatment regimen (11). L. monocytogenes meningoencephalitis and cerebral abscesses have been reported after switching from TMP-SMX to atovaquone for preventing PCP (12). In the present case, L. monocytogenes bacteremia developed after TMP-SMX treatment was switched to atovaquone and did not recur after the administration of TMP-SMX was re-started, suggesting the effectiveness of TMP-SMX in preventing the infection. Ampicillin is the first treatment of choice for L. monocytogenes infection; other therapeutic options include TMP-SMX and meropenem, whereas cephem antibiotics are usually ineffective (2,3). Fourth-generation cephem drugs, which are commonly used in the management of FN, may be inadequate for the initial treatment of L. monocytogenes infection. Therefore, meropenem, which is effective against both listeriosis and FN, should be considered, especially after the use of anti-CD38 antibodies.\n\nIn conclusion, we described a patient with MM who developed L. monocytogenes bacteremia during isatuximab therapy. Isatuximab can cause L. monocytogenes infection and may necessitate prophylaxis with TMP-SMX and dietary guidance.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWe would like to thank the nursing staff who cared for the patient at Kitakyushu Municipal Medical Center and the technical staff at the hospital's bacteriology laboratory.\n==== Refs\n1. Vázquez-Boland JA , Kuhn M , Berche P , et al . Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 14 : 584-640, 2001.11432815\n2. Shoham S , Bartlett JG . Listeria monocytogenes. Johns Hopkins Medicine POC-IT guides [Internet]. [cited 2021 Feb 27]. Available from: https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540318/all/Listeia_monocytogenes\n3. Rivero GA , Torres HA , Rolston KVI , Kontoyiannis DP . Listeria monocytogenes infection in patients with cancer. Diagn Microbiol Infect Dis 47 : 393-398, 2003.14522512\n4. Lischke T , Heesch K , Schumacher V , et al . CD38 controls the innate immune response against Listeria monocytogenes. Infect Immun 81 : 4091-4099, 2013.23980105\n5. Maudet C , Levallois S , Disson O , Lecuit M . Innate immune responses to Listeria in vivo. Curr Opin Microbiol 59 : 95-101, 2021.33307408\n6. Amici SA , Young NA , Narvaez-Miranda J , et al . CD38 is robustly induced in human macrophages and monocytes in inflammatory conditions. Front Immunol 9 : 1593, 2018.30042766\n7. Khan S , Vaisman A , Hota SS , et al . Listeria susceptibility in patients with multiple myeloma receiving daratumumab-based therapy. JAMA Oncol 6 : 293-294, 2020.31774462\n8. Hung DLL , Lau SKP , Woo PCY . Severe sepsis caused by Listeria monocytogenes in a patient given monoclonal antibodies against CD38 and proteosome inhibitor. Infect Microbes Dis 1 : 30-31, 2019.\n9. Horikita F , Hashiguchi J , Nagashima T . Post colonoscopic Listeria monocytogenes meningitis in a patient with multiple myeloma during daratumumab-based therapy. Rinsho Ketsueki (Jpn J Clin Hematol) 61 : 1611-1615, 2020 (in Japanese, Abstract in English).\n10. Deckert J , Wetzel MC , Bartle LM , et al . SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res 20 : 4574-4583, 2014.24987056\n11. Fernàndez-Sabé N , Cervera C , López-Medrano F , et al . Risk factors, clinical features, and outcomes of listeriosis in solid-organ transplant recipients: a matched case-control study. Clin Infect Dis 49 : 1153-1159, 2009.19751149\n12. Adjei PC . Listeria monocytogenes meningoencephalitis and cerebral abscess in a heart transplant recipient. Case Rep Infect Dis 2020 : 8498216, 2020.32655957\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "60(22)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "CD38; Listeria monocytogenes; isatuximab; multiple myeloma", "medline_ta": "Intern Med", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D016470:Bacteremia; D006801:Humans; D008089:Listeria monocytogenes; D008297:Male; D009101:Multiple Myeloma", "nlm_unique_id": "9204241", "other_id": null, "pages": "3605-3608", "pmc": null, "pmid": "34024861", "pubdate": "2021-11-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Listeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma.", "title_normalized": "listeria monocytogenes bacteremia during isatuximab therapy in a patient with multiple myeloma" }

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"medicinalproduct": "POMALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATOVAQUONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATOVAQUONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Listeriosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Ueno T, Ohta T, Imanaga H, Nakazawa M, Sato Y, Sugio Y et al.. Listeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma.. 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"activesubstancename": "POMALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "EPD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POMALIDOMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ELOTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Therapeutic product effect incomplete", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, OHTA T, IMANAGA H, NAKAZAWA M, SATO Y, SUGIO Y, ET AL. LISTERIA MONOCYTOGENES BACTEREMIA DURING ISATUXIMAB THERAPY IN A PATIENT WITH MULTIPLE MYELOMA. INTERN MED. 2021?NO VOLUME:NO PAGINATION", "literaturereference_normalized": "listeria monocytogenes bacteremia during isatuximab therapy in a patient with multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210628", "receivedate": "20210628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19468075, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "OBJECTIVE\nReports of manic episodes associated with the use of cholinesterase inhibitors (including donepezil) are limited. Despite the previous notion of procholinergic drugs potentially inducing depression, the contemporary evidence for cholinesterase inhibitors appears to also indicate a trend for elevated mood (in patients with or without a history of depressive disorder).\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nThe authors report a case of a manic episode with psychotic features associated with the up-titration of donepezil in a patient with Alzheimer's disease and a distant history of major depression but without a preexisting bipolar disorder.\n\n\nCONCLUSIONS\nPathophysiology of donepezil-induced mania appears to contradict the traditional cholinergic-adrenergic hypothesis. Donepezil-associated mania should be suspected after donepezil initiation/dose up-titration when correlated to new onset of mania. Donepezil should be used more cautiously in patients with current or previous mood episodes or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Although this requires further investigation in different patient populations, there may be subtypes of older patients with neurocognitive disorders who are particularly vulnerable to activation effects of cholinesterase inhibitors.", "affiliations": "Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. Electronic address: ahategan@stjosham.on.ca.;Department of Psychiatry/Langley Porter Psychiatric Institute, Consultation/Liaison Service, University of California San Francisco Medical Center, San Francisco, CA, USA.", "authors": "Hategan|Ana|A|;Bourgeois|James A|JA|", "chemical_list": "D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0163-8343", "issue": "38()", "journal": "General hospital psychiatry", "keywords": "Cholinesterase inhibitors; Dementia; Donepezil; Mania; Neurocognitive disorders", "medline_ta": "Gen Hosp Psychiatry", "mesh_terms": "D000341:Affective Disorders, Psychotic; D000368:Aged; D000544:Alzheimer Disease; D001714:Bipolar Disorder; D003865:Depressive Disorder, Major; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines", "nlm_unique_id": "7905527", "other_id": null, "pages": "115.e1-4", "pmc": null, "pmid": "26598289", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Donepezil-associated manic episode with psychotic features: a case report and review of the literature.", "title_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature" }

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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN - HOSP - PSYCHIATRY 2016?38115 E1-115E4. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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"CYMBALTA" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Hategan A, Bourgeois JA.. Donepezil-associated manic episode with psychotic features: A case report and review of the literature. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160125", "receivedate": "20160125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11944631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-00153", "fulfillexpeditecriteria": "2", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypomania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS J, BENAZZI F, ROSSI E. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160209", "receivedate": "20160209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12047471, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-00121", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS J. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. 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DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GENERAL HOSPITAL PSYCHIATRY. 2016?38:115.E1-115.E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160209", "receivedate": "20160209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12047481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-APOTEX-2016AP005930", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078841", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-DONEPEZIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078841", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COGNITIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-DONEPEZIL" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA.. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE.. GEN-HOSP-PSYCHIATRY. 2016?38:115E1-115E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160127", "receivedate": "20160127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11965671, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-PRINSTON PHARMACEUTICAL INC.-2016PRN00017", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, 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null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersexuality", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Jealous delusion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Delusion of grandeur", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN HOSP PSYCHIATRY (DOI: 10.1016/J.GENHOSPPSYCH.2015.09.004). 2016?38:115E1-115E4", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160203", "receivedate": "20160203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11997461, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "CA-MYLANLABS-2016M1002901", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FIBROMYALGIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090521", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090521", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG DAILY AND THEN INCREASED TO 10 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COGNITIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mania", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HATEGAN A, BOURGEOIS JA. DONEPEZIL-ASSOCIATED MANIC EPISODE WITH PSYCHOTIC FEATURES: A CASE REPORT AND REVIEW OF THE LITERATURE. GEN-HOSP-PSYCHIATRY 2016?38:115E1-115E4.", "literaturereference_normalized": "donepezil associated manic episode with psychotic features a case report and review of the literature", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20160125", "receivedate": "20160125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11948423, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" } ]

{ "abstract": "A 60-year-old woman with chronic renal failure due to a polycystic kidney underwent living kidney transplantation. Initial immunosuppressive therapy consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), prednisolone, and basiliximab. Furthermore, rituximab was administered, and double filtration plasmapheresis and plasma exchange were utilized because of ABO-incompatible transplantation, while intravenous immune serum globulin (IVIG) was given because donor specific antibody was positive. Four days after the renal transplantation, the patient developed visual abnormalities, a headache, and paralysis. Then, he became unconscious. Magnetic resonance imaging of the brain demonstrated bilateral posterior vasogenic edema. Our diagnosis was posterior reversible encephalopathy syndrome due to TAC neurotoxicity. After converting TAC to reduced cyclosporine and everolimus, the symptoms rapidly disappeared.", "affiliations": "The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.;The Department of Urology, Hyogo Prefectual Nishinomiya Hospital.", "authors": "Ueda|Norichika|N|;Kawamura|Masataka|M|;Nakazawa|Shigeaki|S|;Hirai|Toshiaki|T|;Kishikawa|Hidefumi|H|;Nishimura|Kenji|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "60(8)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D019520:Living Donors; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0421145", "other_id": null, "pages": "387-92", "pmc": null, "pmid": "25179989", "pubdate": "2014-08", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Posterior reversible encephalopathy syndrome (PRES) after kidney transplantation: a case report.", "title_normalized": "posterior reversible encephalopathy syndrome pres after kidney transplantation a case report" }

[ { "companynumb": "JP-BAXTER-2014BAX065333", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103133", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER AND SOLVENT FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HLA MARKER STUDY POSITIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMAGARD" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103133", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMAGARD" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA N, KAWAMURA M, NAKAZAWA S, HIRAI T, KISHIKAWA H, NISHIMURA K. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES) AFTER KIDNEY TRANSPLANTATION: A CASE REPORT. HINYOKIKA KIYO.ACTA UROLOGICA JAPONICA. 2014 JAN 01;60(8):387-392.", "literaturereference_normalized": "posterior reversible encephalopathy syndrome pres after kidney transplantation a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141111", "receivedate": "20141105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10566960, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "A case of serial killing by poisoning by a 59-year-old practical nurse is discussed. Following a report by an emergency-room doctor of an attempted murder, police performed an investigation into all deaths of patients in the nurse's care. Earlier, a medico-legal cause-of-death investigation had been performed on two of these cadavers, but in the other three cases the death certificate had been issued after a medical investigation only. In two of these latter cases, the body had been cremated, but fixed histological samples taken at medical autopsy were available, while in one case the person had died recently and the body was thereafter exhumed and autopsied. All of the suspected victims were older people who required nursing, and the nurse's course of action was consistent in all cases. In the absence of ordinary post-mortem toxicology samples in the medical cases, extraordinary evidence--paraffin-embedded liver tissue samples originally taken for histology at autopsy--was successfully recovered in two cases and analyzed for drugs. In all five cases, drugs not prescribed to the patient were detected, including digoxin, dixyrazine, citalopram, venlafaxine, and benzodiazepines (diazepam, chlordiazepoxide, temazepam, and oxazepam). The nurse was eventually found guilty of five murders by poisoning, five attempted murders, and three aggravated assaults. The nurse was sentenced to life imprisonment.", "affiliations": "Hjelt Institute, Department of Forensic Medicine, University of Helsinki, Finland.", "authors": "Vuori|Erkki|E|;Pelander|Anna|A|;Rasanen|Ilpo|I|;Juote|Mikko|M|;Ojanperä|Ilkka|I|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/dta.1480", "fulltext": null, "fulltext_license": null, "issn_linking": "1942-7603", "issue": "5(9-10)", "journal": "Drug testing and analysis", "keywords": "drug; exhumation; homicide; paraffin-embedded tissue; poisoning; serial killer", "medline_ta": "Drug Test Anal", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D049249:Exhumation; D005260:Female; D005554:Forensic Medicine; D006708:Homicide; D006801:Humans; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D011041:Poisoning", "nlm_unique_id": "101483449", "other_id": null, "pages": "725-9", "pmc": null, "pmid": "23613335", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": null, "title": "A rare case of serial killing by poisoning.", "title_normalized": "a rare case of serial killing by poisoning" }

[ { "companynumb": "FI-FRI-1000044892", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NORDAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DESMETHYLDIAZEPAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020822", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM HYDROBROMIDE UNK" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20061119" } }, "primarysource": { "literaturereference": "VUORI E, PELANDER A, RASANEN I, JUOTE M, OJANPERA I. A RARE CASE OF SERIAL KILLING BY POISONING. DRUG TESTING AND ANALYSIS. 2013?725?729", "literaturereference_normalized": "a rare case of serial killing by poisoning", "qualification": "1", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20210813", "receivedate": "20130503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9270642, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Smoke inhalation is the most common cause of acute cyanide poisoning in the developed world. Hydroxocobalamin is an antidote for cyanide poisoning. There is little published about human intraosseous antidote administration. We present a case of intraosseous hydroxocobalamin administration in an adult smoke inhalation victim, found in cardiac arrest inside her burning manufactured home. Return of spontaneous circulation was achieved after 20 min of cardiopulmonary resuscitation. Five grams of hydroxocobalamin were subsequently given intraosseously. On hospital arrival, patient was found to have a respiratory-metabolic acidosis. She had red-coloured urine without haematuria, a known sequela of hydroxocobalamin administration. Patient's neurological status deteriorated, and she died 4 days after admission. This case highlights that intraosseously administered hydroxocobalamin seems to adequately flow into the marrow cavity and enter the circulatory system despite the non-compressible glass antidote vial. This appears to be only the second reported human case of intraosseous hydroxocobalamin administration.", "affiliations": "Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA Joshua.Mastenbrook@med.wmich.edu.;Department of Student Affairs, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.", "authors": "Mastenbrook|Joshua|J|http://orcid.org/0000-0002-9928-3674;Zamihovsky|Rachel|R|;Brunken|Nathan|N|;Olsen|Thomas|T|", "chemical_list": "D000931:Antidotes; D003486:Cyanides; D006879:Hydroxocobalamin", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-239523", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(3)", "journal": "BMJ case reports", "keywords": "emergency medicine; poisoning; prehospital; resuscitation; toxicology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000931:Antidotes; D003486:Cyanides; D005260:Female; D005390:Fires; D006323:Heart Arrest; D006801:Humans; D006879:Hydroxocobalamin; D015208:Smoke Inhalation Injury", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33692053", "pubdate": "2021-03-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest.", "title_normalized": "intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest" }

[ { "companynumb": "US-SERB S.A.S.-2123932", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXOCOBALAMIN" }, "drugadditional": null, "drugadministrationroute": "028", "drugauthorizationnumb": "022041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Gas poisoning", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYANOKIT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chromaturia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Mastenbrook J, Zamihovsky R, Brunken N, Olsen T. Intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest. BMJ Case Rep. 2021 Mar 10;14(3):e239523. doi: 10.1136/bcr-2020-239523.", "literaturereference_normalized": "intraosseous administration of hydroxocobalamin after enclosed structure fire cardiac arrest", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20220114", "receivedate": "20220114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20335455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220423" } ]

{ "abstract": "Pancreatic cancer patients have a poor prognosis because of a low rate of resection that results from distant metastases or local advancement. We report a successful case of unresectable locally advanced pancreatic cancer in a patient who was curatively resected after combination therapy with nab-paclitaxel (nab-PTX) and gemcitabine (GEM). A 61-year-old man was referred for treatment of a 45-mm pancreatic tail tumor involving the celiac axis, common hepatic artery, and splenic artery that appeared as an abnormal soft-density mass on imaging. This patient's tumor was defined as unresectable due to local advancement, and, therefore, the powerful combined chemotherapy regimen of nab-PTX with GEM was initiated to allow for possible resection later. After three cycles of chemotherapy, a CT scan revealed that the soft-density mass around the celiac axis and common hepatic artery had dramatically disappeared, and the tumor was then determined to be a resectable lesion. Thus, distal pancreatectomy with en bloc celiac axis resection was performed and curability was achieved. There has been no tumor recurrence or distant metastasis at more than 12 months after surgery, and the patient remains alive at 17 months after initial chemotherapy.", "affiliations": "Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. mhiyoshi@med.miyazaki-u.ac.jp.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.;Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.", "authors": "Hiyoshi|Masahide|M|http://orcid.org/0000-0002-2392-7787;Nanashima|Atsushi|A|;Wada|Takashi|T|;Tsuchimochi|Yuki|Y|;Hamada|Takeomi|T|;Yano|Koichi|K|;Imamura|Naoya|N|;Fujii|Yoshiro|Y|", "chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel", "country": "Japan", "delete": false, "doi": "10.1007/s12328-017-0793-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1865-7265", "issue": "10(6)", "journal": "Clinical journal of gastroenterology", "keywords": "Conversion surgery; Curative resection; Gemcitabine; Locally advanced pancreatic cancer; Nab-paclitaxel", "medline_ta": "Clin J Gastroenterol", "mesh_terms": "D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D002445:Celiac Artery; D003841:Deoxycytidine; D006499:Hepatic Artery; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D017239:Paclitaxel; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D013157:Splenic Artery", "nlm_unique_id": "101477246", "other_id": null, "pages": "551-557", "pmc": null, "pmid": "29086227", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28040257;23907428;26842789;23913634;28736643;25547205;24131140;20134315;11100373;28179342;23660962;28101795;28588798;21620466;27841795;19097774;25258022;17592290;26136371;27304847;28177521;26655559;26350368;25408659;28373919;17981197;1359851;22642850;27022826", "title": "A successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab-paclitaxel with gemcitabine.", "title_normalized": "a successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab paclitaxel with gemcitabine" }

[ { "companynumb": "JP-PFIZER INC-2017512053", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80% DECREASED DOSE WAS ADMINISTERED ON DAY 15 IN THE SECOND AND THIRD CYCLES, (ON DAY 15)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80% DECREASED DOSE WAS ADMINISTERED ON DAY 15 IN THE SECOND AND THIRD CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAYS 1, 8, AND 15 EVERY 4 WEEKS FOR 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAYS 1, 8, AND 15 EVERY 4 WEEKS FOR 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIYOSHI, M.. A SUCCESSFUL CASE OF LOCALLY ADVANCED PANCREATIC CANCER UNDERGOING CURATIVE DISTAL PANCREATECTOMY WITH EN BLOC CELIAC AXIS RESECTION AFTER COMBINATION CHEMOTHERAPY OF NAB-PACLITAXEL WITH GEMCITABINE. CLINICAL JOURNAL OF GASTROENTEROLOGY. 2017?10 (6):551-557", "literaturereference_normalized": "a successful case of locally advanced pancreatic cancer undergoing curative distal pancreatectomy with en bloc celiac axis resection after combination chemotherapy of nab paclitaxel with gemcitabine", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181012", "receivedate": "20171205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14251839, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "Ophthalmic involvement appears rarely in multiple myeloma (MM). Ophthalmic findings are mostly noted as complications caused by disease or treatment. MM-associated with 6th nerve paralysis is a rare entity. Bortezomib, one of the novel agents used to treat MM, has neurotoxic effect and may cause permanent nerve damage. Herein, we report a 50-year-old male patient with MM who developed the 6th nerve paralysis while receiving bortezomib and discuss its relevant causes.", "affiliations": "Division of Haematology, Faculty of Medicine, Bezmialem Vakif University, Vatan Caddesi, Fatih, 34093 Istanbul, Turkey.;Istanbul Training and Research Hospital, Haematology Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Istanbul Training and Research Hospital, Internal Medicine Clinic, Fatih, Istanbul, Turkey.;Faculty of Medicine, Neurology Clinic, Bezmialem Vakif University, Fatih, Istanbul, Turkey.", "authors": "Cetin|Guven|G|;Cem Ar|M|M|;Cerit|Abdullah|A|;Gozubenli|Kubra|K|;Erdem|Simge|S|;Halac|Gulistan|G|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1007/s12288-013-0252-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0971-4502", "issue": "30(Suppl 1)", "journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion", "keywords": "Bortezomib; Multiple myeloma; The 6th nerve paralysis", "medline_ta": "Indian J Hematol Blood Transfus", "mesh_terms": null, "nlm_unique_id": "9425818", "other_id": null, "pages": "70-2", "pmc": null, "pmid": "25332540", "pubdate": "2014-09", "publication_types": "D002363:Case Reports", "references": "15627827;19794956;20977708;11306489;18574024;11130748;12393500", "title": "A rare entity in multiple myeloma: six nerve paralysis.", "title_normalized": "a rare entity in multiple myeloma six nerve paralysis" }

[ { "companynumb": "TR-TAKEDA-2014MPI002840", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021602", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "VIth nerve paralysis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CETIN G, CEM AM, CERIT A, GOZUBENLI K, ERDEM S, HALAC G.. A RARE ENTITY IN MULTIPLE MYELOMA: SIX NERVE PARALYSIS.. INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION. 2014?30 (SUPPL 1):70-72", "literaturereference_normalized": "a rare entity in multiple myeloma six nerve paralysis", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190311", "receivedate": "20190311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16057848, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "Fixed drug eruption (FDE) is an uncommon medication-induced cutaneous reaction. A case of fluconazole-induced FDE is described. A 64-year-old woman presented with eight ovoid hyperpigmented patches on the arms, palm and lower leg that had recurred multiple times at the identical sites at seemingly random intervals over the prior six months. The clinicopathologic diagnosis strongly favored FDE, though the culprit medication remained elusive. Further evaluation and oral rechallenge confirmed the diagnosis of FDE to fluconazole. The patient had not related the eruption to this medication due to the short courses of therapy and prior use without incident. FDE to fluconazole has only been rarely reported in the literature. The presentation and evaluation of FDE is reviewed.", "affiliations": "University of Iowa, Department of Dermatology, Iowa City, IA, USA. hobartwalling@yahoo.com", "authors": "Walling|Hobart W|HW|;Swick|Brian L|BL|", "chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1545-9616", "issue": "9(8)", "journal": "Journal of drugs in dermatology : JDD", "keywords": null, "medline_ta": "J Drugs Dermatol", "mesh_terms": "D000284:Administration, Oral; D000935:Antifungal Agents; D003875:Drug Eruptions; D005260:Female; D015725:Fluconazole; D006801:Humans; D008875:Middle Aged", "nlm_unique_id": "101160020", "other_id": null, "pages": "1025-8", "pmc": null, "pmid": "20684158", "pubdate": "2010-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cutaneous fixed drug eruption to fluconazole.", "title_normalized": "cutaneous fixed drug eruption to fluconazole" }

[ { "companynumb": "US-DRREDDYS-USA/USA/16/0080119", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076658", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TINEA VERSICOLOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fixed drug eruption", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI O, HSU S. CUTANEOUS FIXED DRUG ERUPTION TO FLUCONAZOLE. DERMATOL ONLINE J. 2016;22(4):.", "literaturereference_normalized": "cutaneous fixed drug eruption to fluconazole", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12770266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]

{ "abstract": "OBJECTIVE\nThe current standard treatment for IgA nephropathy relies on steroid and/or immunosuppressive therapy and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB). This study examines the benefits and safety of combining valsartan with clopidogrel and leflunomide as a treatment for progressive IgA nephropathy.\n\n\nMETHODS\nPatients with primary IgA nephropathy, confirmed by renal biopsy, were recruited for this study. Patients were separated into four groups (n = 42 each) after 2 months of run-in period of valsartan treatment. All patients were treated with valsartan alone (Group 1) or valsartan and either clopidogrel (Group 2) or leflunomide (Group 3) or both clopidogrel and leflunomide (Group 4). Each group was followed up for their next 24 months for 24 h urinary protein excretion, serum creatinine and estimated glomerular filtration rate (eGFR) to assess the effect of the treatment. Adverse effects were recorded concurrently to evaluate the safety of the treatment.\n\n\nRESULTS\nOf all 168 patients, 107 were males and 61 were females, with an average age of 33.8 ± 8.79 years. Baseline characteristics were comparable among the four groups (P > 0.05) prior to the experimental treatment. There was a significant (P < 0.05) decrease in 24 h urinary protein excretion after 4 months of experimental treatment. At the end of the 24 months, groups 3 and 4 showed a respective 62.35% and 69.47% reduction in proteinuria. The serum creatinine was significantly higher (P < 0.05) in group 1 and 2 at the end of the follow-up, and their respective eGFR was significantly lower. The incidence of cardiovascular complication was 11.9% and 9.5% for group 1 and 3, respectively.\n\n\nCONCLUSIONS\nThe treatment with Valsartan combined with Clopidogrel and Leflunomide can reduce the urinary proteins loss and renal function deterioration for IgA nephropathy patients and cause minimal adverse reactions. Our study suggests a new clinical treatment option for IgA nephropathy.", "affiliations": "Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.", "authors": "Cheng|Genyang|G|;Liu|Dongwei|D|;Margetts|Peter|P|;Liu|Limin|L|;Zhao|Zhanzheng|Z|;Liu|Zhangsuo|Z|;Tang|Lin|L|;Fang|Yudong|Y|;Li|Haijian|H|;Guo|Yuanyuan|Y|;Chen|Fengmei|F|;Liu|Fengxun|F|", "chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000068756:Valsartan; D000077144:Clopidogrel; D003404:Creatinine; D000077339:Leflunomide; D014633:Valine; D013988:Ticlopidine", "country": "Australia", "delete": false, "doi": "10.1111/nep.12359", "fulltext": null, "fulltext_license": null, "issn_linking": "1320-5358", "issue": "20(2)", "journal": "Nephrology (Carlton, Vic.)", "keywords": "IgA nephropathy; clopidogrel; leflunomide; valsartan", "medline_ta": "Nephrology (Carlton)", "mesh_terms": "D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D002681:China; D000077144:Clopidogrel; D003404:Creatinine; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D006801:Humans; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D007668:Kidney; D000077339:Leflunomide; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011507:Proteinuria; D013777:Tetrazoles; D013988:Ticlopidine; D013997:Time Factors; D016896:Treatment Outcome; D014633:Valine; D000068756:Valsartan", "nlm_unique_id": "9615568", "other_id": null, "pages": "77-84", "pmc": null, "pmid": "25358874", "pubdate": "2015-02", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin A nephropathy.", "title_normalized": "valsartan combined with clopidogrel and or leflunomide for the treatment of progressive immunoglobulin a nephropathy" }

[ { "companynumb": "CN-SA-2015SA019768", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLACEBO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALSARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020839", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG G, LIU D, MARGETTS P, LIU L, ZHAO Z, LIU Z, ET AL. VALSARTAN COMBINED WITH CLOPIDOGREL AND/OR LEFLUNOMIDE FOR THE TREATMENT OF PROGRESSIVE IMMUNOGLOBULIN A NEPHROPATHY. NEPHROLOGY 2015;20(2):77-84. DOI:10.1111/NEP.12359", "literaturereference_normalized": "valsartan combined with clopidogrel and or leflunomide for the treatment of progressive immunoglobulin a nephropathy", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20150220", "receivedate": "20150220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10842280, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Continuous levodopa-carbidopa intestinal gel (LCIG) diminishes daily \"off\" time and dyskinesia in patients with advanced Parkinson's disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J).\n\n\n\nTo report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital.\n\n\n\nLevodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed.\n\n\n\nSixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose (LEDD) had increased by 30% compared to pre-LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died.\n\n\n\nMost patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.", "affiliations": "Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.;HUS Medical Imaging Center Helsinki University Helsinki Finland.;Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Department of Surgery Unit of Therapeutic Endoscopy Helsinki University Helsinki Finland.;Clinical Neurosciences, Neurology Helsinki University Helsinki Finland.", "authors": "Udd|Marianne|M|0000-0001-8916-640X;Lyytinen|Jukka|J|;Eerola-Rautio|Johanna|J|;Kenttämies|Anu|A|;Lindström|Outi|O|;Kylänpää|Leena|L|;Pekkonen|Eero|E|", "chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa", "country": "United States", "delete": false, "doi": "10.1002/brb3.737", "fulltext": "\n==== Front\nBrain BehavBrain Behav10.1002/(ISSN)2157-9032BRB3Brain and Behavior2162-3279John Wiley and Sons Inc. Hoboken 10.1002/brb3.737BRB3737Original ResearchOriginal ResearchProblems related to levodopa‐carbidopa intestinal gel treatment in advanced Parkinson's disease Udd Marianne http://orcid.org/0000-0001-8916-640Xmarianne.udd@hus.fi \n1\nLyytinen Jukka \n2\n\n3\nEerola‐Rautio Johanna \n2\n\n3\nKenttämies Anu \n4\nLindström Outi \n1\nKylänpää Leena \n1\nPekkonen Eero \n2\n\n3\n\n1 \nDepartment of Surgery\nUnit of Therapeutic Endoscopy\nHelsinki University\nHelsinki\nFinland\n\n2 \nClinical Neurosciences, Neurology\nHelsinki University\nHelsinki\nFinland\n\n3 \nDepartment of Neurology\nHelsinki University Hospital and Helsinki University\nHelsinki\nFinland\n\n4 \nHUS Medical Imaging Center\nHelsinki University\nHelsinki\nFinland\n* Correspondence\n\nMarianne Udd, Department of Surgery, Helsinki University Hospital and Helsinki University, Helsinki, Finland.\n\nEmail: marianne.udd@hus.fi\n05 6 2017 7 2017 7 7 10.1002/brb3.2017.7.issue-7e0073731 3 2017 14 4 2017 © 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nContinuous levodopa‐carbidopa intestinal gel (LCIG) diminishes daily “off” time and dyskinesia in patients with advanced Parkinson′s disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG‐J).\n\nAim of the Study\nTo report the clinical outcome of LCIG in patients with advanced PD in the years 2006–2014 at Helsinki University Hospital.\n\nPatients and Methods\nLevodopa‐carbidopa intestinal gel treatment started following PEG‐J placement in patients with advanced PD after successful in‐hospital LCIG trial with a nasojejunal tube. Demographics, PEG‐J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed.\n\nResults [mean (SD)]\nSixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa‐equivalent daily dose (LEDD) had increased by 30% compared to pre‐LCIG LEDD. Sixty patients underwent a total of 156 PEG‐J procedures, and 48 patients (80%) had a total of 143 complications. Forty‐six patients (77%) had 119 PEG‐J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J‐tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow‐up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died.\n\nConclusion\nMost patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG‐J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.\n\ncomplicationduodopaLCIGmortalityParkinson's diseasePEG‐Jweight loss source-schema-version-number2.0component-idbrb3737cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:19.07.2017\n\n\nUdd \nM \n, \nLyytinen \nJ \n, \nEerola‐Rautio \nJ \n, et al. Problems related to levodopa‐carbidopa intestinal gel treatment in advanced Parkinson's disease . Brain Behav . 2017 ;7 :e00737\nhttps://doi.org/10.1002/brb3.737\n==== Body\n1 INTRODUCTION\nPatients with advanced Parkinson's disease (PD) suffer from daily motor fluctuations and dyskinesia. “On” time means periods of good motor control with no disturbing dyskinesia, while “off” time is periods of stiffness and poor mobility. Ideal medication reduces “off” time and minimizes dyskinesia. Combinations of levodopa with carbidopa or benserazide, dopamine agonists, MAO‐B inhibitors and COMT inhibitors are the standard treatment for PD (Horstink et al., 2006). In the advanced disease state, wearing off, on‐off phases, or dyskinesia lead to functional impairment (Ahlskog & Muenter, 2001). The short half‐life of oral levodopa and individual variation of gastric emptying in PD patients cause daily fluctuations in levodopa plasma concentration. Deep brain stimulation (DBS) (Deep Brain Stimulation for Parkinson's Disease Study, Group, 2001), apomorphine infusion (Trenkwalder et al., 2015) and continuous infusion of levodopa‐carbidopa intestinal gel (LCIG) (Nilsson, Nyholm, & Aquilonius, 2001) are device‐aided therapies that can diminish “off” ‐time and dyskinesia in advanced PD. DBS, LCIG and an apomorphine pump are considered only if a combinations of the aforementioned oral drugs is not sufficient. In Finland DBS has been available since 1995, and LCIG since 2006 with 100% reimbursement. Apomorphine pump has been available in Finland since April 2017.\n\nLevodopa‐carbidopa intestinal gel with a levodopa concentration of 20 mg/ml is administered via a portable pump that is connected to the PEG‐J, a percutaneous endoscopic gastrostomy (PEG) with a thinner inner J‐tube placed in the proximal jejunum. LCIG treatment ensures continuous dopaminergic stimulation and it significantly reduces daily motor fluctuations and dyskinesia compared to oral levodopa (Olanow et al., 2014). However, complications with the tube or the pump are common, presenting in 40%–96% of patients (Devos, 2009; Fernandez et al., 2013, 2015; Nyholm et al., 2008; Pickut, van der Linden, Dethy, Van De Maele, & de Beyl, 2014).\n\nThe aim of the present study was to analyze the outcome of long‐term LCIG treatment in advanced PD, paying special attention to complications and discontinuation of the treatment in the clinical setting.\n\n2 PATIENTS AND METHODS\nAltogether, 60 patients with advanced PD received LCIG therapy at Helsinki University Hospital between 2006 and 2014. A neurologist selected candidates for LCIG treatment i.e., patients who reported substantial daily motor fluctuations and dyskinesia that could not be sufficiently controlled with oral PD medication. Severe dementia, ongoing psychosis, and unresponsiveness to levodopa were exclusion criteria. The total daily oral doses of levodopa, amantadine, dopamine agonists and MAO‐B‐ and COMT‐inhibitors were converted to a morning dose and continuous daily infusion of LCIG. To assess the response to LCIG, the patients were admitted to neurological ward and had a nasojejunal tube (Flocare Bengmark® 10Fr, Nutricia, Netherlands) for 4–6 days of testing. A radiologist positioned the tube near the ligamentum of Treitz under fluoroscopic control. LCIG was administered with a pump via the nasojejunal tube, and the response to LCIG was assessed with diaries. If this testing phase was successful, the patient had a PEG‐J.\n\n2.1 PEG‐J procedure\nA PEG‐J tube (Freka® 15 Fr or 20 Fr PEG ‐tube and Freka® 9 Fr intestinal Tube, Fresenius Kabi, Cheshire, UK) was inserted under endoscopic and fluoroscopic control by gastroenterologic surgeons in the endoscopic unit using the pull‐through method (Gauderer, Ponsky, & Izant, 1980). Antibiotic prophylaxis (1.5 g cefuroxime, Zinacef®, GlaxoSmithKline, Espoo, Finland) and local anesthesia with lidocaine (10 mg/ml Lidocain®, Orion, Espoo, Finland) were administered, and conscious sedation was provided by an anesthesiologist. After placement of the PEG tube, the inner J tube was moved near the ligamentum of Treitz with rat‐tooth forceps. If this failed, a guidewire (Jagwire, Boston Scientific, Alajuela, Costa Rica) and a triple lumen balloon were passed to the duodenum, the balloon was retrieved and the J tube inserted over the guidewire. The position of the inner tube was controlled under fluoroscopy. The PEG‐J was connected to a portable infusion pump (CADD legacy 1400 Duodopa pump, Smits Medical ASD, St Paul, MN, USA).\n\n2.2 LCIG infusion in practice\nThe LCIG (20 mg/ml of levodopa and 5 mg/ml carbidopa; Duodopa®, Abbvie) dose optimization was carried out in the neurologic ward. All oral PD medication was usually stopped, with the exception of high‐dose dopamine agonists with positive clinical response. The morning bolus was followed by a continuous infusion. Additional doses were administered by the patient when they felt they were entering an “off” phase. Usually, infusion lasted 16 hr, supplemented with a sustained‐release oral dose of levodopa for the night. If necessary, night infusion was applied, with the infusion rate being about 40%–60% less than infusion during the day. Control phone calls were planned for 2–4 weeks after and control visits for 6 months after initiation of LCIG for clinical evaluation in the outpatient clinic. The patients were advised to gradually increase the daily infusion if several extra doses had to be taken daily. In cases of inner tube problems, the patients were advised to administer LCIG via PEG to the gastric space or to restart oral medication. If an infusion problem occurred, a scheduled admission to the neurological ward was arranged, with a subsequent endoscopic procedure to correct the tube problem.\n\n2.3 Data collection at baseline and during the follow‐up\nThe following data were collected: duration of PD, age at onset of PD, preceding PD medication, ASA (Physical Status Classification of the American Society of Anesthesiologists) class, body mass index (BMI), concomitant diseases, details of the PEG‐J procedure, living conditions (alone, with a spouse, in institutional care), a mini‐mental state examination (with MMSE ≥25 indicating normal cognition), a Hoehn and Yahr scale assessment, neurosurgical contraindications (coagulopathy, cognitive impairment). Also daily hours on LCIG, LCIG doses after 6 months, and any additional oral medication data were collected. At the end of the follow‐up in November 2015, information about weight loss (weight change as a percentage during follow‐up), living conditions and discontinuation of the LCIG treatment was gathered. The number of contacts with the stoma nurse, data of PEG‐J related (tube occlusion, accidental removal of inner tube, dislocation of the inner tube backwards into the stomach, tube breakage), peristomal (stoma leakage, granulation tissue around stoma, skin excoriation, abscess or infection, PEG tube hat buried in gastric wall, i.e., buried bumper syndrome (BBS)), or other (≥5% weight loss, gastric ulceration caused by inner tube, neurological) complications and mortality were collected from the patient files for the study. Underweight was defined as a BMI of <18.5 m2/kg, normal weight as a BMI 18.5–25 m2/kg, and overweight as a BMI of >25 m2/kg.\n\n2.4 Informed consent statement\nThe study was approved by the hospital ethics committee. Data extraction occurred retrospectively from hospital medical records. According to Finnish law, retrospective research using hospital medical files does not require informed consent from the study subjects.\n\n2.5 Statistics\nThe results are reported as means and standard deviation (SD). The significance of differences in categorical data was determined using Fisher's exact test. The Mann–Whitney U test was used to discover the differences in continuous variables. A level of p < .05 was regarded as statistically significant, and two tailed tests were used. Statistical calculations were generated using IBM SPSS Statistics 21 (International Business Machines Corporation, Endicott, NY, USA).\n\n3 RESULTS\nMean age at onset of PD was 56 (8) years, and the duration of PD was 11 (4) years before LCIG treatment. There were 32 men (53%) and 28 women (47%) with a mean age of 68 (7) years, and 27 participants (45%) were 70 or older. Baseline characteristics are presented in Table 1. The mean Hoehn and Yahr score in the “on” phase was 2.7 (0.7). At the onset of LCIG treatment, all the patients had been on levodopa only, or a combination of amantadine, a dopamine agonist, and MAO‐B‐ or COMT‐ inhibitors, with a mean levodopa‐equivalent daily dose (LEDD) of 1,266 (441) mg. Ten patients (17%) were taking only levodopa, 18 (31%) were taking two drugs and 30 (52%) had three or more different drugs daily. An MMSE test was performed on 48 patients prior to LCIG treatment. The mean MMSE score was 26 (3). Altogether, 29 patients refused or had contraindications for DBS treatment. The details of the PEG‐J procedure are presented in Table 2.\n\nTable 1 Baseline characteristics of PD patients on LCIG treatment\n\nDemographics\t\nn = 60\t\nASA I\t0\t\nASA II\t3 (5%)\t\nASA III\t51 (85%)\t\nASA IV\t6 (10%)\t\nCoronary/‐heart disease\t17 (28%)\t\nDiabetes\t8 (13%)\t\nPsychiatric diagnosis\t11 (18%)\t\nMMSE ≤24\t11 (23%)\t\nHoehn and Yahr score on phase ≥4\t6 (10%)\t\nLives with a spouse\t44 (73%)\t\nLives alone\t12 (20%)\t\nIn sheltered housing with assistance\t4 (7%)\t\nWalker as mobility aid\t15 (25%)\t\nWheelchair or crutches as mobility aid\t6 (11%)\t\nPD, Parkinson's disease; LCIG, levodopa‐carbidopa intestinal gel; ASA, data of physical status classification of the American Society of Anesthesiologists ASA class; MMSE, mini‐mental state examination.\n\nJohn Wiley & Sons, LtdTable 2 PEG‐J placement procedure in 60 patients\n\nTime from nasojejunal test tube placement to PEG‐J placement; days; mean (SD)\t6.5 (2.7)\t\nTotal hospital stay, days; mean (SD)\t11 (4)\t\nHospital stay after PEG‐J placement, days\t3.9 (3.9)\t\nLength of the procedure, min; mean (SD)\t31 (16)\t\nAntibiotic prophylaxis\t48 (87%)\t\nPEG‐J: Fresenius Freka® 15 Fr\t51 (85%)\t\nPEG‐J: Boston® 20 Fr\t9 (15%)\t\nInner tube in the descending or transverse duodenum\t6 (10%)\t\nInner tube in the ligament of Treitz\t54 (90%)\t\nPEG‐J, percutaneous endoscopic gastrostomy with jejunal tube; SD, standard deviation.\n\nJohn Wiley & Sons, Ltd3.1 LCIG dose\nAfter discharge, 51 patients (85%) had daily LCIG infusion, and nine cases (15%) were 24 hr a day. The mean daily LCIG dose was 1,651 (595) mg. At 6 months, 42 patients (78%) had daily infusion and 12 (22%) had 24‐hr infusion. In most cases (44), the LEDD had increased by 505 (304) mg compared with the baseline. In nine patients, the LEDD had decreased by 255 (126) mg. Doses of LCIG at baseline and 6 months were: morning bolus 191 (67) mg vs. 170 (71) mg, continuous infusion 73 (27) mg/hr vs. 81 (29) mg/hr (6 a.m.–10 p.m.) and 57 (26) mg/hr vs. 72 (43) mg/hr (10 p.m.–6 a.m.), correspondingly.\n\nAt the end of the follow‐up period of 33 (24) months, 38 patients (63%) were on LCIG, 7 (12%) had been on LCIG until death, 13 (22%) had discontinued LCIG and were alive, and two patients (3%) discontinued LCIG and died later.\n\nThirty‐two patients were on LCIG for more than 2 years, and 12 patients for more than 4 years. Fifty‐three patients (90%) felt that LCIG treatment still substantially alleviated motor symptoms, when questioned at 6 months and beyond.\n\n3.2 Changes in weight, living conditions and need for walking devices during LCIG treatment\nAt baseline, the mean BMI of the patients was 24.7 (4.2) kg/m2: only three patients (5%) were underweight, 31 (57%) were normal weight and 26 (43%) were overweight. At the end of the follow‐up, eight patients (13%) were underweight, 31 (52%) were normal weight and 21 (35%) were overweight. The weight change as a percentage was −3.3% (10.7%) in 25.7 (23.1) months. Eighteen patients (30%) had weight loss of ≥5%, and in 12 patients (20%), weight loss was ≥10%. One patient had fatal weight loss despite discontinuation of LCIG. Body CT did not show any malignancy. The autopsy failed to reveal any clear cause for his deterioration. Two patients had peripheral neuropathy prior to LCIG, probably due to diabetes and spinal stenosis.\n\nAt the end of the follow‐up, 38 patients (66%) were still living at home with their spouse or alone, 17 (29%) were in institutional care, (mainly sheltered housing with 24‐hr assistance), and three patients had intervals at home and in institutions. Nine patients originally living with their spouse (21%) and four originally living alone (33%) had moved to sheltered housing. The need to use a walker increased by 40%, (n = 21, 37%) and a wheelchair by 50% (n = 6; 11%), and two patients became bedridden.\n\n3.3 Discontinuation\nCognitive decline or dementia at the baseline or appearance of these symptoms during follow up were the most common causes of infusion withdrawal, occurring in seven patients after 27 (25) months of LCIG. In two bedridden patients living in institutions, LCIG was stopped after 38 (12) months. One patient was suffering from stoma problems and discontinued the treatment at 19 months. Two patients (3.3%) stopped LCIG after 3 months and 5 months because of inefficacy. One patient subjectively felt dizziness during LCIG treatment and decided to discontinue the LCIG infusion after a month, although clinical examination showed no signs of either postural instability or orthostatic hypotension. Altogether, after a mean of 21 (21) months, LCIG was discontinued in 15 patients, and in 11 cases the reason was recurrent removal of the inner tube by the patient.\n\n3.4 Complications\nSixty patients underwent a total of 156 endoscopic procedures. An additional 96 endoscopic procedures following 60 PEG‐J placements are presented in Table 3, and complications related to LCIG treatment are shown in Table 4. There were 48 patients (80%) with a total of 143 complications, and only 12 patients with no complications. Altogether, 46 patients (77%) had a total of 119 PEG‐J or peristomal complications, and 22 (37%) had a total of 25 other complications. On average, patients had 2.4 (2.1) complications. In 30 days after PEG‐J, 11 patients (18%) had complication (six peristomal infections, one granulation, one gastric hematoma, one nonspecific infection, one knot and occlusion, and one disorientation). Thirty‐one patients visited a stoma nurse a total of 121 times. Accidental removal of the inner tube occurred significantly more often in patients with cognitive decline (MMSE <24), than in those without it: 8 (73%) vs. 12 (35%); p = .034. There were no peritonitis cases during the follow‐up.\n\nTable 3 Additional procedures after PEG‐J placement in the endoscopy unit (n = 96)\n\nHospital stay, days; mean(SD)\t2.3 (3.7)\t\nLength of the procedure, min; mean (SD)\t19 (11)\t\nIndications for the procedure\t\nAccidental removal of inner tube\t37 (38%)\t\nTube occlusion\t27 (29%)\t\nTube break\t14 (15%)\t\nStoma leak\t4 (4%)\t\nDislocation of the inner tube backwards into the stomach\t2 (2%)\t\nThicker PEG‐J for nutrition\t4 (4%)\t\nDiscontinuation of the treatment\t8 (8%)\t\nProcedures: n = 96\t\nInner tube placement or exchange\t45 (47%)\t\nPEG‐J tube exchange\t25 (26%)\t\nTesting the tube, checking with fluoroscopy or gastroscopy, exchanging the caps\t13 (14%)\t\nRemoval of the PEG‐J systema\n\t13 (14%)\t\nPEG‐J, percutaneous endoscopic gastrostomy‐jejunal tube; SD, standard deviation.\n\na Of 15 patients discontinuing LCIG, two patients used the PEG for nutrition and it was not removed.\n\nJohn Wiley & Sons, LtdTable 4 Complications in 60 patients on LCIG\n\nComplication\t\nn = 60\t\nPeristomal complications:\t\nBuried PEG bumper\t1 (1%)\t\nSkin problems, leaking stoma\t12 (20%)\t\nNonspecific infection\t4 (7%)\t\nSkin infection, abscess\t5 (8%)\t\nGranulation tissue\t21 (35%)\t\nTube complications:\t\nTube occlusion\t13 (22%)\t\nAccidental removal of inner tube\t23 (38%)\t\nDislocation of the inner tube backwards into the stomach\t5 (8%)\t\nTube break\t11 (18%)\t\nOther complications:\t\nWeight loss ≥5%\t18 (30%)\t\nNeurologic symptoms\t3 (5%)\t\nPump issue\t3 (5%)\t\nPeritonitis\t0\t\nLCIG, levodopa‐carbidopa intestinal gel.\n\nJohn Wiley & Sons, Ltd3.5 Mortality\nAccording to death certificates provided by Statistics Finland, there were no PEG‐J related complications or deaths. Altogether, nine patients died, seven of whom were on LCIG until death. Two patients died 3.7 and 21.5 months after discontinuing LCIG, respectively. The time from the start of LCIG to death was 26.6 (14) months. The causes of death were defined by clinical examination in four patients and by clinical autopsy in five patients. The immediate causes of death were pneumonia (n = 4), advanced PD (n = 2), coronary heart disease or insufficiency (n = 2) and pulmonary embolism (n = 1). The underlying causes of death were PD (n = 7) and coronary heart disease (n = 2).\n\nBody mass index at onset was significantly higher in those alive at the end of the follow‐up compared to those who died: 25.1(4.4) vs. 22.2(3.4); p = .043. Similarly, BMI at the latest follow‐up visit was significantly higher in those alive at the end of the follow‐up than in those who died during the follow‐up, at 24.3 (4.0) vs. 18.9 (3.1); p = .001. Four underweight patients (44%) died, compared to five patients (8%) with normal weight or overweight; p = .013.\n\n4 DISCUSSION\nLevodopa‐carbidopa intestinal gel treatment has proved to be effective in reducing levodopa‐related dyskinesia and diminishing off time compared to oral medication, leading to improvement in the quality of life (Antonini, Yegin, Preda, Bergmann, & Poewe, 2015; Lopiano et al., 2016; Olanow et al., 2014; Wirdefeldt, Odin, & Nyholm, 2016). We present data on LCIG therapy, focusing on complications. The majority of our patients were satisfied with the infusion during follow‐up. There were, however, numerous tube and stoma complications related to LCIG, as reported previously (Fernandez et al., 2015; Lang et al., 2016; Nilsson et al., 2001).\n\nIn most of our patients, LEDD was increased at 6 months compared to baseline. The LEDD increase may be caused by disease progression. We had 12 patients (20%) with their LCIG pump running for 24 hr. That is slightly more than previously reported by Devos et al. (10% LCIG for 24 hr) (Devos, 2009). One study showed a quite stable LEDD on LCIG for 12 months (Antonini et al., 2015).\n\nIn some studies, dementia was an exclusion criterion, and only patients with an MMSE of 28–29 were included (Epstein et al., 2016; Fernandez et al., 2015). In a French multicentre study (Devos, 2009), 50% of the patients on LCIG had cognitive disorders suggestive of PD dementia. We found LCIG suitable for patients with mild dementia living with a motivated spouse. However, there was more accidental tube removal in patients with cognitive decline. Hence, patients with dementia living alone appear not to be suitable candidates for LCIG. Despite the LCIG treatment, 29% of our patients were in institutional care, mainly sheltered housing with 24‐hr assistance at the end of the follow‐up.\n\nSeveral technical problems and complications increase the annual admission rate and contact with the hospital (Nyholm et al., 2008). Complications with the PEG‐J tube (Devos, 2009; Fernandez et al., 2013; Nyholm et al., 2008) are similar to complications related to PEG for feeding purposes (Schapiro & Edmundowicz, 1996; Udd et al., 2015). The risk of peritonitis has varied between zero and 4% (Devos, 2009; Epstein et al., 2016; Lang et al., 2016; Palhagen et al., 2016), and other serious complications like colonic perforations, gastropleural fistula (Klostermann et al., 2012) and liver injury (Pickut et al., 2014), have also been described. In our material, we did not have any peritonitis, nor any need for emergency abdominal surgery due to LCIG complications. A peristomal infection risk of 8% is comparable with the literature: 10%–20% (Devos, 2009; Epstein et al., 2016; Fernandez et al., 2015; Olanow et al., 2014). Inner tube complications were mostly accidental removal, kinking or dislocation of the tube occurring during the LCIG treatment in physically active patients, sometimes suffering from disorientation (Devos, 2009; Fernandez et al., 2013; Nyholm et al., 2008; Pickut et al., 2014). We did not find any cases of inner tube‐induced duodenal decubitus ulcer (Martino et al., 2016), or bezoar sometimes present in these patients. Our results showed that 13 patients had a total of 27 tube occlusions, and eight of them (61%) had altogether ten knots in the inner tube. Previously, only three case reports of five patients with knotting of the inner tube had been published (del‐Hoyo‐Francisco et al., 2015; Krones, Zollner, & Petritsch, 2012; Nyholm et al., 2008). The Freka® intestinal tube has an angled, C‐shaped tip, and this may predispose the tube to knots (Figure 1). The present results showing that removal of the inner tube occurs more often in patients with dementia are supported by previous findings (Devos, 2009). Logically, among patients with no dementia, the rate is lower (Epstein et al., 2016; Fernandez et al., 2015).\n\nFigure 1 Naive and knotted jejunal tube\n\nThe triangular external fixation plate of the Freka® PEG‐J tube is suboptimal, because it glides along the PEG tube, allowing the PEG to move back and forth. This movement may even predispose the patient to peritonitis in the first days when the stoma is maturing (Epstein et al., 2016). The skin around the peristomal area may become irritated by leaking gastric fluids. Granulation formation needs referral to a stoma nurse. Granulation tissue was more common in our patients (35%) compared to other series (20%–22%) (Epstein et al., 2016; Lang et al., 2016).\n\nWeight loss is an adverse event increasing the risk of death, and is partly associated with the natural course of PD. One third of our patients had ≥5% weight loss during the follow‐up with one fatal weight loss despite discontinuation of LCIG. Decreased weight has been observed in 5%–10% of LCIG patients (Antonini et al., 2015; Merola et al., 2016). The mechanism for weight loss in LCIG remains ambiguous. Monitoring weight during LCIG treatment is essential to avoid serious weight loss.\n\nEighty percent of the patients had complications leading to multiple endoscopic procedures, but still 90% were satisfied with the treatment. Some of the complications may therefore be related to the suboptimal devices and tubes. A new T‐port was found to be well tolerated, and it had a low number of tube problems, but proper cleaning and local treatment of the stoma site were necessary (van Laar, Nyholm, & Nyman, 2016). The use of a T‐port is not widely spread, though.\n\nCurrently, there are no guidelines for withdrawal of LCIG. If the patient is bedridden, disoriented and already needs maximal care, LCIG probably may not give any significant health benefit. Several removals of the inner tube by a patient during the treatment suggest that the mental condition of that patient has significantly deteriorated. In these cases, discontinuation of LCIG should be individually considered. Further, several replacements of the inner tube increase the burden of already limited hospital resources. Continuous weight loss can even be a fatal complication, and therefore needs monitoring. Close co‐operation between neurological and endoscopic units is required, and units must be prepared for common and recurrent PEG‐J problems when LCIG treatment for advanced PD is carried out.\n\nCONFLICTS OF INTEREST\nMarianne Udd received a one‐month researcher's salary from the Helsinki University Hospital Research Fund. The authors have no conflicts of interest to disclose.\n\nACKNOWLEDGMENTS\nAll co‐authors have reviewed and approve the content of the manuscript. The Brain and Behaviour requirements for authorship have been met, and there is no ghost‐writing by anyone not named on the author list. We confirm that the manuscript is not under review and has not been accepted for publication elsewhere.\n==== Refs\nREFERENCES\n\n\nAhlskog , J. E. \n, & \nMuenter , M. D. \n (2001 ). Frequency of levodopa‐related dyskinesias and motor fluctuations as estimated from the cumulative literature . 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Continuous intrajejunal infusion of levodopa‐carbidopa intestinal gel for patients with advanced Parkinson's disease: A randomised, controlled, double‐blind, double‐dummy study . Lancet Neurology , 13 (2 ), 141 –149 .24361112 \n\n\nPalhagen , S. E. \n, \nSydow , O. \n, \nJohansson , A. \n, \nNyholm , D. \n, \nHolmberg , B. \n, \nWidner , H. \n, … \nMarshall , T. S. \n (2016 ). Levodopa‐carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open‐label prospective observational study of effectiveness, tolerability and healthcare costs . Parkinsonism & Related Disorders , 29 , 17 –23 .27318707 \n\n\nPickut , B. A. \n, \nvan der Linden , C. \n, \nDethy , S. \n, \nVan De Maele , H. \n, & \nde Beyl , D. Z. \n (2014 ). Intestinal levodopa infusion: The Belgian experience . Neurological Sciences , 35 (6 ), 861 –866 .24379105 \n\n\nSchapiro , G. D. \n, & \nEdmundowicz , S. A. \n (1996 ). Complications of percutaneous endoscopic gastrostomy . Gastrointestinal Endoscopy Clinics of North America , 6 (2 ), 409 –422 .8673334 \n\n\nTrenkwalder , C. \n, \nChaudhuri , K. R. \n, \nGarcia Ruiz , P. J. \n, \nLeWitt , P. \n, \nKatzenschlager , R. \n, \nSixel‐Doring , F. \n, … \nWenzel , K. \n (2015 ). Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease–Clinical practice recommendations . Parkinsonism & Related Disorders , 21 (9 ), 1023 –1030 .26189414 \n\n\nUdd , M. \n, \nLindstrom , O. \n, \nMustonen , H. \n, \nBack , L. \n, \nHalttunen , J. \n, & \nKylanpaa , L. \n (2015 ). Assessment of indications for percutaneous endoscopic gastrostomy–development of a predictive model . Scandinavian Journal of Gastroenterology , 50 (2 ), 245 –252 .25540954 \n\n\nWirdefeldt , K. \n, \nOdin , P. \n, & \nNyholm , D. \n (2016 ). Levodopa‐carbidopa intestinal gel in patients with Parkinson's Disease: A systematic review . CNS Drugs , 30 (5 ), 381 –404 .27138916\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "7(7)", "journal": "Brain and behavior", "keywords": "LCIG; PEG‐J; Parkinson's disease; complication; duodopa; mortality; weight loss", "medline_ta": "Brain Behav", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D012189:Retrospective Studies; D016896:Treatment Outcome; D015431:Weight Loss", "nlm_unique_id": "101570837", "other_id": null, "pages": "e00737", "pmc": null, "pmid": "28729942", "pubdate": "2017-07", "publication_types": "D016428:Journal Article", "references": "22298101;19253412;24379105;18382177;23192929;24361112;25545465;6780678;17038031;11575287;27421834;11903087;23287001;27030949;27614656;8673334;27138916;26189414;28729942;26213103;25540954;11391738;25585993;26695437;27215392;25952811;27318707", "title": "Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease.", "title_normalized": "problems related to levodopa carbidopa intestinal gel treatment in advanced parkinson s disease" }

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{ "abstract": "Tumor necrosis factor (TNF) is a major cytokine in the pathogenesis of inflammatory bowel disease (IBD), and TNF inhibition is a cornerstone of contemporary IBD therapy. However, paradoxical induction of IBD has recently been reported upon treatment of rheumatologic disorders with TNF inhibitors. In previous cases, induction of IBD was associated with one single drug and IBD was successfully managed by switching TNF inhibitors. We report the case of a patient with juvenile rheumatoid arthritis under long-term treatment with etanercept. After switching TNF inhibition to adalimumab, symptoms of Crohn's disease (CD) occurred and the diagnosis of CD was established by endoscopy. Further treatment with adalimumab and subsequently infliximab aggravated the abdominal symptoms, necessitating ileocecal resection, after which symptoms resolved for several months. Etanercept treatment due to recurrent rheumatologic symptoms was followed by recurrent CD symptoms and findings, which resolved upon discontinuation of etanercept. This case suggests that induction, aggravation and recurrence of IBD can be rare class effects of TNF inhibition.", "affiliations": "Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Department of Visceral and Transplant Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.;Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.", "authors": "Zeitz|Jonas|J|;Enderlin|Susann|S|;Biedermann|Luc|L|;Turina|Matthias|M|;Leibl|Sebastian|S|;Prakash|Meher|M|;Rogler|Gerhard|G|;Misselwitz|Benjamin|B|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000381637", "fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000381637crg-0009-0106Published online: April, 2015New Onset, Aggravation and Recurrence of Crohn's Disease upon Treatment with Three Different Tumor Necrosis Factor Inhibitors Zeitz Jonas aEnderlin Susann bBiedermann Luc aTurina Matthias cLeibl Sebastian dPrakash Meher aRogler Gerhard aMisselwitz Benjamin a*aDivision of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandbDivision of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandcDepartment of Visceral and Transplant Surgery, University Hospital Zurich, University of Zurich, Zurich, SwitzerlanddDivision of Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland*Benjamin Misselwitz, Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091 Zurich (Switzerland), E-Mail benjamin.misselwitz@usz.chJan-Apr 2015 24 4 2015 24 4 2015 9 1 106 112 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Tumor necrosis factor (TNF) is a major cytokine in the pathogenesis of inflammatory bowel disease (IBD), and TNF inhibition is a cornerstone of contemporary IBD therapy. However, paradoxical induction of IBD has recently been reported upon treatment of rheumatologic disorders with TNF inhibitors. In previous cases, induction of IBD was associated with one single drug and IBD was successfully managed by switching TNF inhibitors. We report the case of a patient with juvenile rheumatoid arthritis under long-term treatment with etanercept. After switching TNF inhibition to adalimumab, symptoms of Crohn's disease (CD) occurred and the diagnosis of CD was established by endoscopy. Further treatment with adalimumab and subsequently infliximab aggravated the abdominal symptoms, necessitating ileocecal resection, after which symptoms resolved for several months. Etanercept treatment due to recurrent rheumatologic symptoms was followed by recurrent CD symptoms and findings, which resolved upon discontinuation of etanercept. This case suggests that induction, aggravation and recurrence of IBD can be rare class effects of TNF inhibition.\n\nKey Words\nInflammatory bowel diseaseCrohn's diseaseTumor necrosis factor inhibitionAutoimmune-like syndromes\n==== Body\nIntroduction\nTumor necrosis factor (TNF) plays a central role in the pathogenesis of inflammatory bowel disease (IBD), and the introduction of TNF inhibitors has substantially broadened the therapeutic options in IBD [1]. Available monoclonal antibodies which are effective for the treatment of Crohn's disease (CD) and ulcerative colitis include infliximab and adalimumab [2]. In contrast etanercept, a fusion protein of the human soluble TNF receptor p75 with the Fc fragment of human immunoglobulin G1, was shown to be safe but not effective in CD [3]. The reasons for this differential effect of infliximab/adalimumab and etanercept are not understood, but might include complement-dependent cytotoxicity and induction of apoptosis by infliximab/adalimumab, but not by etanercept. Vice versa, lymphotoxin is bound and neutralized by etanercept, but not the antibodies [4].\n\nTherapy with TNF inhibitors has an acceptable safety profile and besides infusion reactions, the adverse events of TNF inhibitor treatment are mainly infectious complications, including tuberculosis, as might be expected from their mode of action [5]. Paradoxical immune activation by TNF inhibitors has also been described, and autoimmune disorders, including psoriasis, vasculitis, systemic lupus erythematosus, interstitial lung disease and sarcoidosis, have been reported as adverse events of TNF inhibitor treatment [6]. The mechanisms of autoimmune-like syndromes during TNF blockade have not be clarified, but autoimmune-like syndromes might be caused by cytotoxicity of the drugs, increase of interferon-α levels by TNF, dysregulation of T cells and unrecognized infectious complications. Furthermore, direct or indirect effects of TNF inhibitors might induce exposure towards autoantigens, including self-DNA or self-RNA, which could act as endogenous ligands of Toll-like receptors and lead to autoimmunity [7].\n\nParadoxical induction of IBD by the TNF inhibitor etanercept has been described in seminal case reports and systematic analyses [8, 9]. IBD as an adverse event of treatment is not limited to etanercept treatment, since recent case series also included cases of IBD induced by infliximab or adalimumab [10]. However, in the cases described, new-onset IBD could be treated by switching TNF inhibitors, usually to infliximab or adalimumab, and idiosyncratic effects of the culprit drugs could not be excluded. We report a case with new onset, progression and recurrence of CD upon treatment with three different TNF inhibitors, suggesting paradoxical induction of IBD as a class effect of TNF inhibitors.\n\nCase Presentation\nA 19-year-old man presented to our division for the management of severe right lower quadrant pain. His previous history was remarkable for juvenile rheumatoid arthritis starting at 12 years of age, involving the sacroiliac and mandibular joint as well as the right ankle and hip. He was tested positive for HLA-B27, but tests for antinuclear antibodies and rheumatoid factor proved to be negative. At 16 years of age etanercept 50 mg s.c. was started which initially relieved the symptoms, so the dose was reduced to every 2 weeks after 1 year of treatment. However, 1 year later the joint pain recurred and was refractory to etanercept dose escalation (weekly) and add-on naproxen. Two months before the onset of abdominal pain the treatment regime was changed to adalimumab 40 mg s.c. every 2 weeks and the patient remained free of rheumatologic problems for the next year.\n\nDuring evaluation for abdominal pain, lower right quadrant tenderness and a palpable tumor were noted. Blood work revealed systemic inflammation (C-reactive protein 46 mg/l and leukocytosis with 13.7 × 109 leucocytes per liter with 84% neutrophils). Ultrasound and computed tomography suggested terminal ileitis and abdominal lymphadenopathy. Stool tests for microorganisms including Clostridium difficile were negative. Colonoscopy demonstrated an ulcerated ileocecal valve with a narrow opening that could not be intubated. Histology confirmed granulomatous inflammation and acute inflammation, and all tests for infectious diseases, including acid-fast staining, mycobacteria cultures and immunohistochemistry for cytomegalovirus, were negative.\n\nSince the patient's presentation was consistent with new-onset CD, we continued adalimumab treatment and started budesonide at 9 mg/day. Subsequently, abdominal pain improved; however, surveillance of small bowel inflammation by abdominal ultrasound continued to show wall thickening >6 mm, consistent with active inflammation, and budesonide was increased to 15 mg/day. Due to recurrent abdominal symptoms treatment was switched to infliximab 5 mg/kg body weight, but abdominal pain only temporarily improved and recurred only 3 months after starting infliximab. The patient was now complaining of constant abdominal pain and had lost 12 kg of body weight (body mass index 16 kg/m2). Magnetic resonance imaging revealed chronic terminal ileitis and a complex fistula system. In hospital parenteral nutrition was started, infliximab was stopped, and 9 months after the onset of abdominal pain, right-sided colectomy with an ileocolic anastomosis was performed (fig. 1). The immediate postoperative course was unremarkable; the patient remained free of symptoms and body weight increased.\n\nThree months after surgery, joint inflammation recurred in the hips, shoulders, right foot, lumbar spine and sacroiliac joint. Due to limited therapeutic options for the treatment of ileosacral arthritis, etanercept 50 mg s.c. weekly was restarted after careful discussion with the patient. Etanercept immediately relived joint pains, but 14 days after restarting the TNF inhibitor abdominal pain recurred, accompanied by an increase in calprotectin levels. Colonoscopy revealed multiple ulcers at the ileocolic anastomosis and histology confirmed ulceration. Abdominal pain slowly resolved after etanercept had been discontinued. The clinical course is summarized in figure 2.\n\nDiscussion and Conclusions\nIn our patient induction, aggravation and recurrence of CD occurred during treatment with three different TNF inhibitors (adalimumab, infliximab and etanercept). According to the Naranjo algorithm [11], a consensus algorithm to estimate the probability of causality in a suspected drug-induced clinical event, a definite association between TNF inhibitor treatment and CD as an adverse drug event is present in our patient (10 out of 13 possible points). Importantly, there has been no alternative explanation of IBD in our patient with a negative family history for IBD and only a brief period of naproxen treatment, which had been discontinued weeks before the initial onset of abdominal pain. However, some limitations of the Naranjo algorithm exist and some ambiguity remains: Following a recent analysis of new-onset IBD as an adverse event of TNF inhibitor treatment, we did not score juvenile idiopathic arthritis as an alternative explanation for IBD in our patient [12]. The possibility of joint involvement as an extraintestinal manifestation of IBD preceding the onset of CD for several years seems unlikely but cannot be rigorously excluded. For consistency, the Naranjo score was applied as in the previous larger study [12].\n\nProof for an association of IBD with TNF treatment is strongest for etanercept. In addition to seminal case reports, larger case series have now been published. Thereby, in a report from a European etanercept registry for treatment of juvenile idiopathic arthritis, 13 cases of new-onset IBD (including 9 cases with CD) were noted. The authors calculated a 43-fold increased risk for IBD compared to the control population. Of note, 10 of the patients were subsequently treated with another TNF inhibitor (5 each, infliximab and adalimumab) [13]. A second case series from France identified 8 patients with juvenile idiopathic arthritis and etanercept treatment (5 cases with CD and 3 cases with unclassified colitis). The clinical course of all patients was favorable upon discontinuation of etanercept; 6 of 8 patients were successfully treated with infliximab [9].\n\nWithin the last years, infliximab and adalimumab have increasingly been used for the treatment of rheumatic disorders and, likely due to increased patient exposure, evidence of paradoxical induction of IBD was also observed for these antibodies. A recent French series described 16 patients with rheumatoid arthritis and new-onset IBD under TNF inhibitor treatment (14 cases with etanercept, 2 with adalimumab). Similarly to the previous series, most of the patients had CD (8 and 6 cases with CD and Crohn's-like disease, respectively, and 1 case with unclassified colitis), and all patients could be successfully treated by switching the TNF inhibitor to infliximab or adalimumab [10]. Finally, a recent publication analyzing all adverse events regarding TNF inhibitors reported to the FDA described 158 cases of new-onset IBD. Most of the cases involved etanercept, but 28 cases of infliximab, 24 cases of adalimumab and 1 case of golimumab were listed. 111 of the associations were regarded as ‘possible’ and 47 as ‘probable’ according to the Naranjo algorithm [12].\n\nTaken together, the various case reports and case series reporting new-onset IBD upon etanercept treatment strongly suggest that etanercept can rarely trigger IBD in susceptible patients. Paradoxical induction of IBD by infliximab and adalimumab is also likely, even though the evidence is weaker. Therefore, TNF inhibition seems to have paradoxical pro-inflammatory properties which are usually extinguished by its anti-inflammatory effects. It is tempting to speculate that etanercept, which has no proven therapeutic effects against CD, can cause overt mucosal inflammation more often than infliximab or adalimumab, which are highly effective against IBD. Following this model, only in those few patients for whom the inflammatory process is completely resistant to TNF inhibition can inflammation progress to clinically overt CD.\n\nSpecific risk factors for the development of paradoxical IBD in patients exposed to etanercept or infliximab/adalimumab remain to be elucidated. In addition, it is unknown why TNF inhibition would trigger mainly CD or unclassified colitis. In any case, our report adds evidence regarding the great variability in the pathways utilized for the inflammatory process in different patients and suggests that TNF can be protective in at least a few patients [14].\n\nThe management of IBD cases triggered by TNF inhibitors is largely identical to that of classical IBD cases, and in addition to discontinuation of the offending drug, standard IBD treatment should be applied [15]. When appropriate, switching the TNF inhibitor also seems to be safe; however, if symptoms persist or worsen even upon treatment with a second inhibitor (as in our patient), alternative treatment options should be pursued.\n\nIn summary, we present the first case of a patient in whom the onset, aggravation and recurrence of CD were triggered by TNF inhibition with three different TNF inhibitors, and our results point to CD as a rare adverse event and a class effect of TNF inhibitors.\n\nAuthor Contributions\nB. Misselwitz and J. Zeitz drafted the manuscript. G. Rogler, S. Enderlin, L. Biedermann, M. Turina, S. Leibl and M. Prakash edited the manuscript for important intellectual content. M. Prakash, B. Misselwitz, M. Turina and S. Leibl prepared the figures. All authors read and approved the final version of the manuscript.\n\nDisclosure Statement\nB. Misselwitz has received travel grants from Vifor and Novartis and speaker's honoraria from MSD and Tillots. L. Biedermann has received research support from UCB, travel grants from MSD, Abbvie and Vifor, and fees for consulting/advisory boards from MSD, Abbvie and UCB. G. Rogler has consulted to Abbott, Abbvie, Boehringer, Calypso, FALK, Genentech, Essex/MSD, Novartis, Pfizer, Roche, UCB, Takeda (Switzerland), Tillots and Vifor, has received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB, and Vifor, and has received educational grants and research grants from Abbot, Abbvie, Ardeypharm, Essex/MSD, FALK, Flamentera, Novartis, Roche, Tillots, UCB and Zeller. J. Zeitz has received a research grant from Abbvie. S. Leibl, S. Enderlin, M. Turina and M. Prakash have no conflict of interests.\n\nFig. 1 Surgical specimen. a Macroscopic view. b Hematoxylin and eosin staining at 5-fold magnification revealing a fissure, transmural inflammation and architectural changes of the surrounding mucosa. c Hematoxylin and eosin staining at 100-fold magnification revealing non-caseating granulomas within a draining lymph node.\n\nFig. 2 a Overview of the clinical course. The time course of various pharmacological treatments and clinical symptoms is indicated. The time points of the first (C1) and second (C2) colonoscopy and the time point of surgery are marked. b Serum levels of C-reactive protein (CRP). c Levels of stool calprotectin.\n==== Refs\nReferences\n1 Sandborn WJ Targan SR Biologic therapy of inflammatory bowel disease Gastroenterology 2002 122 1592 1608 12016425 \n2 Ford AC Sandborn WJ Khan KJ Hanauer SB Talley NJ Moayyedi P Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis Am J Gastroenterol; quiz 660 2011 106 644 659 \n3 Sandborn WJ Hanauer SB Katz S Safdi M Wolf DG Baerg RD Tremaine WJ Johnson T Diehl NN Zinsmeister AR Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial Gastroenterology 2001 121 1088 1094 11677200 \n4 Marotte H Cimaz R Etanercept – TNF receptor and IgG1 Fc fusion protein: is it different from other TNF blockers? Expert Opin Biol Ther 2014 14 569 572 24611432 \n5 Targownik LE Bernstein CN Infectious and malignant complications of TNF inhibitor therapy in IBD Am J Gastroenterol; quiz 1843 2013 108 1835 1842 \n6 Perez-Alvarez R Perez-de-Lis M Ramos-Casals M BIOGEAS study group: Biologics-induced autoimmune diseases Curr Opin Rheumatol 2013 25 56 64 23114587 \n7 Prinz JC Autoimmune-like syndromes during TNF blockade: does infection have a role? Nat Rev Rheumatol 2011 7 429 434 21448162 \n8 Wiegering V Morbach H Dick A Girschick HJ Crohn's disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature Rheumatol Int 2010 30 801 804 19506877 \n9 Dallocchio A Canioni D Ruemmele F Duquesne A Scoazec JY Bouvier R Paraf F Languepin J Wouters CH Guillot M Quartier P Bader-Meunier B SOFREMIP: Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study Rheumatology (Oxford) 2010 49 1694 1698 20472717 \n10 Toussirot E Houvenagel E Goëb V Fouache D Martin A Le Dantec P Dernis E Wendling D Ansemant T Berthelot JM Bader-Meunier B Kantelip B Le CRI: Development of inflammatory bowel disease during anti-TNF-α therapy for inflammatory rheumatic disease: a nationwide series Joint Bone Spine 2012 79 457 463 22088934 \n11 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508 \n12 Krishnan A Stobaugh DJ Deepak P Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis Rheumatol Int 2015 35 661 668 25228459 \n13 Van Dijken TD Vastert SJ Gerloni VM Pontikaki I Linnemann K Girschick H Armbrust W Minden K Prince FH Kokke FT Nieuwenhuis EE Horneff G Wulffraat NM Development of inflammatory bowel disease in patients with juvenile idiopathic arthritis treated with etanercept J Rheumatol 2011 38 1441 1446 21459936 \n14 Slebioda TJ Kmiec Z Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease Mediators Inflamm 2014 2014 325129 25045210 \n15 Dignass A Van Assche G Lindsay JO Lémann M Söderholm J Colombel JF Danese S D'Hoore A Gassull M Gomollón F Hommes DW Michetti P O'Morain C Oresland T Windsor A Stange EF Travis SP European Crohn's and Colitis Organisation (ECCO): The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management J Crohns Colitis 2010 4 28 62 21122489\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-0631", "issue": "9(1)", "journal": "Case reports in gastroenterology", "keywords": "Autoimmune-like syndromes; Crohn's disease; Inflammatory bowel disease; Tumor necrosis factor inhibition", "medline_ta": "Case Rep Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101474819", "other_id": null, "pages": "106-12", "pmc": null, "pmid": "26034472", "pubdate": "2015", "publication_types": "D002363:Case Reports", "references": "21122489;21459936;12016425;19506877;22088934;21448162;11677200;25045210;20472717;24611432;24042192;25228459;7249508;21407183;23114587", "title": "New Onset, Aggravation and Recurrence of Crohn's Disease upon Treatment with Three Different Tumor Necrosis Factor Inhibitors.", "title_normalized": "new onset aggravation and recurrence of crohn s disease upon treatment with three different tumor necrosis factor inhibitors" }

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{ "abstract": "We present a case of severe lactic acidosis due to exacerbation of asthma in presence of normal tissue perfusion and oxygenation in a 35-year-old woman with poorly controlled asthma. After admission, she was treated continuously with inhalation of salbutamol (a beta-agonist) resulting in lactic acidosis, which was misinterpreted as treatment failure. The lactic acidosis reversed on discontinuation of the inhalation therapy. Although lactic acidosis is a rare complication to inhalation of beta-agonists, it is important for the clinicians to recognize this.", "affiliations": "Anæstesi- og operationsklinikken, Juliane Marie Centret, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark. kimekelund@gmail.com", "authors": "Ekelund|Kim|K|;Følsgaard|Søren|S|", "chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol", "country": "Denmark", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-5782", "issue": "175(3)", "journal": "Ugeskrift for laeger", "keywords": null, "medline_ta": "Ugeskr Laeger", "mesh_terms": "D000140:Acidosis, Lactic; D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000328:Adult; D000420:Albuterol; D001249:Asthma; D005260:Female; D006801:Humans; D009330:Nebulizers and Vaporizers; D016896:Treatment Outcome", "nlm_unique_id": "0141730", "other_id": null, "pages": "112-4", "pmc": null, "pmid": "23331939", "pubdate": "2013-01-14", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lactic acidosis in a patient with exercabation of asthma receiving inhalation therapy.", "title_normalized": "lactic acidosis in a patient with exercabation of asthma receiving inhalation therapy" }

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{ "abstract": "BACKGROUND\nAcute lymphoblastic leukemia is an invasive malignancy which ought to be treated with several cytotoxic medications. Vincristine-based regimen is among the most commonly used regimens for the treatment of adult acute lymphoblastic leukemia. Peripheral neuropathy caused by vincristine provides a limitation in dose administration and can influence the treatment outcome and patient's quality of life.\n\n\nMETHODS\nIleus and constipation occurred as a result of autonomic neuropathy in a 58-year-old man who underwent vincristine-based regimen for acute lymphoblastic leukemia treatment. Despite the administration of several laxative agents for constipation, the complication did not improve. So metoclopramide as a prokinetic agent was administered intravenously, and patient bowel movement and defecation started after 24 h.\n\n\nCONCLUSIONS\nThere is no approved protocol for vincristine-induced autonomic neuropathy treatment; thus, prokinetic agents such as metoclopramide can be considered as an option for ileus treatment after ruling out the possibility of bowel obstruction. Prophylactic stool softeners should be administrated in all patients undergoing chemotherapy with vincristine to prevent gastrointestinal motility disorders.", "affiliations": "Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Research Center for Rational Use of Drugs, and Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.", "authors": "Masoumi|Hamidreza T|HT|;Hadjibabaie|Molouk|M|;Zarif-Yeganeh|Morvarid|M|https://orcid.org/0000-0003-2196-4119;Khajeh|Behrouz|B|https://orcid.org/0000-0002-5645-4955;Ghavamzadeh|Ardeshir|A|", "chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D005765:Gastrointestinal Agents; D014750:Vincristine; D008787:Metoclopramide", "country": "England", "delete": false, "doi": "10.1177/1078155217746228", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "25(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Vincristine; acute lymphoblastic leukemia; ileus; metoclopramide; neuropathy", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D003248:Constipation; D005765:Gastrointestinal Agents; D006801:Humans; D045823:Ileus; D008297:Male; D008787:Metoclopramide; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014750:Vincristine", "nlm_unique_id": "9511372", "other_id": null, "pages": "507-511", "pmc": null, "pmid": "29224457", "pubdate": "2019-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of vincristine-induced ileus with metoclopramide: A case report.", "title_normalized": "treatment of vincristine induced ileus with metoclopramide a case report" }

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{ "abstract": "We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.", "affiliations": "Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Pediatric Neurology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.;Division of Pediatric Ophthalmology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.", "authors": "Horvath|Gabriella-Ana|GA|;Hukin|Juliette|J|;Stockler-Ipsiroglu|Sylvia G|SG|;Aroichane|Maryam|M|", "chemical_list": "D000927:Anticonvulsants; D013654:Taurine; D050644:Succinate-Semialdehyde Dehydrogenase; D020888:Vigabatrin", "country": "Germany", "delete": false, "doi": "10.1055/s-0036-1583183", "fulltext": null, "fulltext_license": null, "issn_linking": "0174-304X", "issue": "47(4)", "journal": "Neuropediatrics", "keywords": null, "medline_ta": "Neuropediatrics", "mesh_terms": "D000592:Amino Acid Metabolism, Inborn Errors; D000927:Anticonvulsants; D002648:Child; D002658:Developmental Disabilities; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D058499:Retinal Dystrophies; D050644:Succinate-Semialdehyde Dehydrogenase; D013654:Taurine; D020888:Vigabatrin", "nlm_unique_id": "8101187", "other_id": null, "pages": "263-7", "pmc": null, "pmid": "27104484", "pubdate": "2016-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.", "title_normalized": "eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency" }

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NEUROPEDIATRICS. 2016 APR 22;.", "literaturereference_normalized": "eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20170922", "receivedate": "20170922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13999228, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "CA-LUNDBECK-DKLU1081340", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENZYME ABNORMALITY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VIGABATRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020427", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SABRIL" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal dystrophy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HORVATH G, HUKIN J, STOCKLER-IPSIROGLU S, AROICHANE M. 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{ "abstract": "Reported here is the case of a severely disabled young girl who developed Fanconi syndrome secondary to long-term valproic acid administration, ultimately leading to hypophosphatemic rickets. Although nephrocalcinosis is not a common feature in patients with proximal tubulopathy, the patient presented also with this condition, and the concomitant use of another anticonvulsant might have potentiated this condition. The purpose of this report is to increase awareness among healthcare providers of such rare but significant complications associated with anticonvulsants.", "affiliations": "Pediatrics Department, McMaster University, Hamilton, Canada. kelau@mcmaster.ca", "authors": "Lau|Keith K|KK|;Papneja|Koyelle|K|", "chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2012()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000927:Anticonvulsants; D002648:Child; D003937:Diagnosis, Differential; D005198:Fanconi Syndrome; D005260:Female; D005632:Fructose; D006801:Humans; D009397:Nephrocalcinosis; D012279:Rickets; D012640:Seizures; D000077236:Topiramate; D014635:Valproic Acid", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "22665570", "pubdate": "2012-02-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15025812;18436283;16997051;19201620;11322374;21586883;21874139;20466520;19302942;20304335;17515139;7688423;7624000;12042105;21638910;8108303;21717384;20686423;17877442;6782217;11473672;15816962;20888032;11442157;12435575;16450323;15785938;3146224;15230715;3124010;12366731;12363104", "title": "Anticonvulsant-induced rickets and nephrocalcinosis.", "title_normalized": "anticonvulsant induced rickets and nephrocalcinosis" }

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"drugauthorizationnumb": "078791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX SODIUM ER" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARNITINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 2 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARNITINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, 2 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM CARBONATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CARBONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG IN MORNING, 12.5 MGIN EVENING AND 25 MG IN NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypophosphataemic rickets", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephrocalcinosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fanconi syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAU KK, PAPNEJA K.. ANTICONVULSANT-INDUCED RICKETS AND NEPHROCALCINOSIS. BMJ CASE REPORTS. 2012;1-4", "literaturereference_normalized": "anticonvulsant induced rickets and nephrocalcinosis", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20150320", "receivedate": "20150320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10934557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "CA-RANBAXY-2013US-65561", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARNITINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, 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"drugdosagetext": "125 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CARBONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG A.M, 12.5 MG PM AND 25 MG NOCTE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091037", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125MG AM, 62.5MG PM, AND 125MG NOCTE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "11.4", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypophosphataemic rickets", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Femur fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fanconi syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephrocalcinosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypophosphataemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAU KK, PAPNEJA K. ANTICONVULSANT-INDUCED RICKETS AND NEPHROCALCINOSIS. BMJ CASE REP. 2012?FEB 25:4 PAGES", "literaturereference_normalized": "anticonvulsant induced rickets and nephrocalcinosis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151006", "receivedate": "20130305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9138302, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "To assess the impact of the 2011 changes in pediatric single-ingredient liquid acetaminophen product packaging and standardization of the acetaminophen concentration (160 mg/5 mL) on poison control center exposures due to medication errors.\n\n\n\nNational Poison Data System (NPDS) data from January 1, 2007, through December 31, 2016, were used to identify medication error exposures involving single-ingredient liquid acetaminophen in children younger than 12 years of age. Surveys were conducted through 6 regional poison control centers to obtain additional information on a subset of exposures.\n\n\n\nThe annual frequency of NPDS exposures due to medication errors with single-ingredient liquid acetaminophen products was 8260 ± 670 exposures/year during 2007-2011. Children <2 years of age accounted for 66% of exposures. The overall rate of exposures fell to 6669 ± 662 during 2012-2016 (19% decrease; P = .005). Four percent of exposures led to health care facility referrals. Caregivers involved with exposures in children <2 years of age cited health professionals as the source of dosing information in only 69% of cases despite the absence of specific dosing directions for these children on product labels.\n\n\n\nImplementation of a single concentration for pediatric liquid acetaminophen products and packaging changes were associated with a decrease in medication errors reported to poison control centers. Medication errors are particularly problematic for children <2 years of age, for whom there are no specific labeled dosing instructions. Improved efforts to provide caregivers with dosing instructions for these children are encouraged.", "affiliations": "Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, Palos Verdes, Calif.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo. Electronic address: kate.reynolds@rmpdc.org.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colo.", "authors": "Brass|Eric P|EP|;Reynolds|Kate M|KM|;Burnham|Randy I|RI|;Green|Jody L|JL|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1016/j.acap.2018.03.001", "fulltext": null, "fulltext_license": null, "issn_linking": "1876-2859", "issue": "18(5)", "journal": "Academic pediatrics", "keywords": "acetaminophen; medication error; poison prevention; regional poison control center", "medline_ta": "Acad Pediatr", "mesh_terms": "D000082:Acetaminophen; D017677:Age Distribution; D018712:Analgesics, Non-Narcotic; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D004348:Drug Labeling; D004363:Drug Utilization; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008508:Medication Errors; D019064:Product Packaging", "nlm_unique_id": "101499145", "other_id": null, "pages": "563-568", "pmc": null, "pmid": "29522886", "pubdate": "2018-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Medication Errors With Pediatric Liquid Acetaminophen After Standardization of Concentration and Packaging Improvements.", "title_normalized": "medication errors with pediatric liquid acetaminophen after standardization of concentration and packaging improvements" }

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{ "abstract": "A case of a 36-year old woman with HER2-positive early breast cancer treated with adjuvant trastuzumab left ventricle dysfunction and cardiac arrest in ventricular fibrillation mechanism is presented. After having been successfully resuscitated, trastuzumab therapy was withheld, pharmacotherapy (beta-blocker, ACE-I) implemented and ICD was implanted. Echocardiography performed 6 months later, revealed normal systolic function of the left ventricle. The patient died despite further oncologic treatment due to progression of the disease. The authors discuss the approach to this dramatic but lone cardiac side effect of trastuzumab treatment.", "affiliations": "Oddział Kardiologii, Wojewódzki Szpital Specjalistyczny im. M. Kopernika, Łódź. gpiotr4@wp.pl", "authors": "Piotrowski|Grzegorz|G|;Gawor|Rafał|R|;Słomka|Robert|R|;Banasiak|Maciej|M|;Strzelecki|Paweł|P|;Gawor|Zenon|Z|;Potemski|Piotr|P|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Receptor, ErbB-2; D000068878:Trastuzumab", "country": "Poland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0022-9032", "issue": "70(7)", "journal": "Kardiologia polska", "keywords": null, "medline_ta": "Kardiol Pol", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001145:Arrhythmias, Cardiac; D001943:Breast Neoplasms; D017147:Defibrillators, Implantable; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018719:Receptor, ErbB-2; D000068878:Trastuzumab", "nlm_unique_id": "0376352", "other_id": null, "pages": "756-7", "pmc": null, "pmid": "22825957", "pubdate": "2012", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardioverter-defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type-2 breast cancer.", "title_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer" }

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"activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "761074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM/KILOGRAM, Q3W", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE, 4 CYCLES OF NEOADJUVANT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "761074", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM/KILOGRAM, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE, 4 CYCLES OF NEOADJUVANT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Left ventricular dysfunction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PIOTROWSKI, G.. CARDIOVERTER-DEFIBRILLATOR IN THE TREATMENT OF ARRHYTHMIA INDUCED BY TRASTUZUMAB USED IN THE ADJUVANT SETTING IN A PATIENT WITH POSITIVE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE-2 BREAST CANCER.. POLISH CARDIOLOGY. 2012?70 (7):756-7", "literaturereference_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20191218", "receivedate": "20191218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17172176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "PL-PFIZER INC-2019263409", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/KG, CYCLIC (ADJUVANT IMMUNOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (4 CYCLES OF NEOADJUVANT AT CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/KG, CYCLIC (LOADING DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (4 CYCLES OF NEOADJUVANT AT CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (4 CYCLES OF NEOADJUVANT AT CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Left ventricular dysfunction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PIOTROWSKI, G.. CARDIOVERTER-DEFIBRILLATOR IN THE TREATMENT OF ARRHYTHMIA INDUCED BY TRASTUZUMAB USED IN THE ADJUVANT SETTING IN A PATIENT WITH POSITIVE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE-2 BREAST CANCER. POLISH CARDIOLOGY. 2012?70 (7):756-757", "literaturereference_normalized": "cardioverter defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type 2 breast cancer", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20190814", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16474433, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "A 30-year-old Vietnamese woman, about 19 weeks pregnant, was admitted for acute cerebral infarction with stenosis of the left middle cerebral artery (LMCA), tuberculous meningitis, and miliary tuberculosis. Treatment with heparin, quadruple anti-tuberculosis therapy, and dexamethasone afforded prompt symptomatic improvement. However, she delivered a stillbirth, after which there was recurrence of acute cerebral infarction with LMCA occlusion, sinus thrombosis, and cranial base inflammation. A thrice-weekly 100 mg dose of intrathecal isoniazid (INH) improved the signs of meningeal inflammation. The patient was discharged ambulatory after 7 months. In refractory tuberculous meningitis, multimodal therapy with intrathecal INH and steroids should be considered.", "affiliations": "Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Neurology, Tottori Prefectural Central Hospital, Japan.;Department of Brain and Neurosciences, Division of Neurology, Faculty of Medicine, Tottori University, Japan.", "authors": "Nakatani|Yuko|Y|;Suto|Yutaka|Y|;Fukuma|Kazuki|K|;Yamawaki|Mika|M|;Sakata|Ryoichi|R|;Takahashi|Shotaro|S|;Nakayasu|Hiroyuki|H|;Nakashima|Kenji|K|", "chemical_list": "D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000995:Antitubercular Agents; D003907:Dexamethasone; D007538:Isoniazid", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.56.6945", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2842084610.2169/internalmedicine.56.6945Case ReportIntrathecal Isoniazid for Refractory Tuberculous Meningitis with Cerebral Infarction Nakatani Yuko 1Suto Yutaka 12Fukuma Kazuki 12Yamawaki Mika 1Sakata Ryoichi 12Takahashi Shotaro 12Nakayasu Hiroyuki 1Nakashima Kenji 21 Department of Neurology, Tottori Prefectural Central Hospital, Japan2 Department of Brain and Neurosciences, Division of Neurology, Faculty of Medicine, Tottori University, JapanCorrespondence to Dr.　Yutaka Suto, sutoyutaka.i@gmail.com\n\n15 4 2017 56 8 953 957 25 12 2015 26 7 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 30-year-old Vietnamese woman, about 19 weeks pregnant, was admitted for acute cerebral infarction with stenosis of the left middle cerebral artery (LMCA), tuberculous meningitis, and miliary tuberculosis. Treatment with heparin, quadruple anti-tuberculosis therapy, and dexamethasone afforded prompt symptomatic improvement. However, she delivered a stillbirth, after which there was recurrence of acute cerebral infarction with LMCA occlusion, sinus thrombosis, and cranial base inflammation. A thrice-weekly 100 mg dose of intrathecal isoniazid (INH) improved the signs of meningeal inflammation. The patient was discharged ambulatory after 7 months. In refractory tuberculous meningitis, multimodal therapy with intrathecal INH and steroids should be considered. \n\nintrathecal isoniazidtuberculous meningitiscerebral infarctionpregnancy\n==== Body\nIntroduction\nTuberculous meningitis is a serious disease with high rates of mortality and residual neurologic deficits (1). Although the British Infection Society has recommended treatment regimens (2), additional high-strength modalities may be needed in some serious cases. We herein report a case of tuberculous meningitis in which remission was achieved not with the recommended treatment but with intrathecal administration of isoniazid (INH).\n\nCase Report\nThe patient was a 30-year-old Vietnamese woman with no relevant medical history who was studying in Japan. She presented with common cold symptoms for 2 weeks and a fever of about 38℃, followed by right hemiplegia. These prompted consultation and subsequent admission to our hospital. The patient had undergone fertility treatment at a private obstetrics-gynecology clinic and was about 19 weeks pregnant. She had hyperemesis with a poor nutritional status, however, no weight gain during pregnancy was observed.\n\nThe general physical findings were as follows: height 157 cm, weight 52 kg, body mass index 21.1, blood pressure 116/57 mmHg, heart rate 128/min, respiration rate 30/min, body temperature 38.0℃, and oxygen saturation of 95%. There were no pertinent thoracic or abdominal findings, except for the signs of pregnancy. The neurologic findings were lucid consciousness, spontaneous pain in the posterior cervical region, nuchal rigidity, right central facial palsy, right hemiplegia (Brunnstrom stage I in the arm and fingers, Brunnstrom stage II in the leg), hyperreflexia of the right upper and lower limbs, and right leg sensory deficit. Blood inflammatory markers showed a white blood cell count of 6,920 /μL and C-reactive protein of 3.42 mg/dL. Blood biochemistry results indicated mild liver dysfunction (aspartate aminotransferase 43 IU/L, alanine aminotransferase 46 IU/L) and undernutrition, with albumin at 2.3 g/dL. There were no abnormal findings related to the kidney or pancreas function. Testing for human immunodeficiency virus was negative.\n\nThe cerebrospinal fluid (CSF) findings were as follows: pale yellow color, initial pressure 290 mmH2O, final pressure 150 mmH2O, cell count 100 /μL with a lymphocyte-to-polymorphonuclear leukocyte ratio of 67:33, protein 229 mg/dL, sugar 11 mg/dL, and positive Ziehl-Neelsen staining. Cranial magnetic resonance imaging (MRI) on diffusion-weighted images revealed acute cerebral infraction of the left putamen; magnetic resonance angiography (MRA) revealed stenosis of the left middle cerebral artery (LMCA) (Fig. 1a and b). Ground glass opacities in both lung fields were noted on chest radiograph and computed tomography (CT) (Fig. 1c and d). Cerebral infarction secondary to vasculitis from tuberculous meningitis and miliary tuberculosis were suspected.\n\nFigure 1. Radiologic imaging findings in a 30-year-old woman with refractory tuberculous meningitis. (a) Cranial MRI diffusion-weighted image shows acute cerebral infarction of the left putamen. (b) MRA shows stenosis in the horizontal segment of the left middle cerebral artery (arrow). (c) Chest radiograph shows miliary shadows in both lung fields. (d) On chest CT, there were diffuse ground glass opacities in both lung fields. MRI: magnetic resonance imaging, MRA: magnetic resonance angiography, CT: computed tomography\n\nFig. 2 shows the clinical course of the patient's hospitalization. Treatment was started with dexamethasone (19.6 mg/day) and four anti-tuberculosis drugs: INH (200 mg/day), rifampicin (RFP) (450 mg/day), ethambutol (EB) (750 mg/day), and pyrazinamide (PZA) (1.2 g/day). Because bacterial meningitis could not be ruled out, meropenem (6 g/day) was also administered. Taking into consideration the patient's pregnancy, acute cerebral infarction was treated with continuous heparin infusion at 10,000 units/day. Based on positive tubercle bacilli DNA on polymerase chain reaction and positive culture for Mycobacterium tuberculosis, the patient was given a definitive diagnosis of tuberculous meningitis. After five days of treatment, liver dysfunction ensued. When the liver dysfunction improved after a week, the administration of the four drugs was continued, with PZA being replaced by levofloxacin (LVFX) (500 mg/day). The fever and right hemiplegia promptly improved. Although Ziehl-Neelsen staining was performed only once and showed positivity and susceptibility to all anti-tuberculous drugs, the presence of Mycobacterium tuberculosis in the CSF was sustained for up to one month, despite the administration of anti-tuberculosis drugs.\n\nFigure 2. Clinical course of a 30-year-old woman with refractory tuberculous meningitis. INH: isoniazid, RFP: rifampicin, EB: ethambutol, PZA: pyrazinamide, LVFX: levofloxacin, SM: streptomycin\n\nOn hospital day 25, at 22 weeks and 1 day of gestation, the patient gave birth to a stillborn. Examination of the uterine contents revealed tubercule bacilli, confirming an intrauterine infection. After the stillbirth, the fever and meningitis signs recurred. Despite treatment with 5 anti-tuberculosis agents (with the addition of streptomycin at 1 g/day) and restarting dexamethasone administration (19.6 mg/day), no improvement in the signs of meningeal irritation was observed. On hospital day 33, aphasia and right hemiplegia appeared; on hospital day 37, right abducens nerve palsy developed. Repeat cranial MRI revealed recurrent cerebral infarction on the left parietal lobe; MRA showed peripheral occlusion of the horizontal segment of the LMCA. Findings indicative of inflammation of the cranial base and lateral sinus thrombosis were also observed (Fig. 3). These were treated with edaravone and heparin; administration of aspirin (100 mg/day) was also continued to prevent recurrence.\n\nFigure 3. Cranial MRI findings of recurrent cerebral infarction in tuberculous meningitis. (a) Diffusion-weighted images show infarcted area in the left posterior limb of the internal capsule, left corona radiata, and left parietal lobe. (b) MRA shows occlusion of the left middle cerebral artery (arrow head). (c) Enhanced T1-weighted images show inflammatory changes in the base of the brain (encircled area) and venous sinus thrombosis (arrow). MRI: magnetic resonance imaging, MRA: magnetic resonance angiography\n\nHowever, the meningitis symptoms persisted and did not improve despite increasing the INH dosage from 300 mg/day to 500 mg/day. Therefore, intrathecal administration of 100 mg of INH 3 times per week was started. Furthermore, 15 mL of CSF was intermittently drained by lumbar puncture to relieve intracranial pressure. The signs of meningeal irritation started to improve after starting intrathecal INH. Serial cranial MRI indicated resolution of the venous sinus thrombosis and reduction of the inflammatory findings in the cranial base (Fig. 4). On hospital day 98, the visual acuity on the left decreased, suggesting left optic neuritis caused by inflammation of the cranial base. As the possibility of optic neuropathy could not be ruled out, EB was discontinued. Intrathecal INH administration was tapered to once a week and eventually was discontinued as the patient's symptoms improved.\n\nFigure 4. Cranial MRI after intrathecal administration of INH for tuberculous meningitis complicated by cerebral infarction. Enhanced T1-weighted images show improvement of the inflammatory changes in the base of the brain (encircled area) and resolution of sinus thrombosis (arrow). MRI: magnetic resonance imaging, INH: isoniazid\n\nThe patient was discharged for home on hospital day 191. Three anti-tuberculosis drugs (INH, RFP, and LVFX) were continuously administered for 1 year. The residual neurologic deficits were mild aphasia, decreased visual acuity on the left side, and hypoesthesia in both legs, which was suspected to be secondary to INH. Nevertheless, the patient was able to independently engage in her activities of daily living. Cranial MRI 2 years after onset showed that the occlusion in the horizontal segment of the LMCA was unchanged; therefore, the administration of aspirin (100 mg/day) was continued to prevent the recurrence of cerebral infarction. Approximately 2.5 years later, the patient returned to her home country. She was able to walk without assistance and carry out her usual duties and activities.\n\nDiscussion\nTuberculous meningitis causes inflammatory changes in the base of the brain, leading to vasculitis, cranial polyneuritis, and obstructive hydrocephalus (3). Cerebral infarction as a complication is widely known to be associated with a poor prognosis (4).\n\nIn the present case, we referred to the recommendations of the British Infection Society (2) and administered a four-drug combination of INH, RFP, EB, and PZA. Although the guidelines for treating tuberculosis in pregnant patients state that PZA should be avoided as much as possible because its safety has not been established (5), we decided to continue PZA to save the mother's life, as this was a severe case of tuberculosis. Based on a report by Thwaites et al. (6), we also administered corticosteroids. The recommended treatment led to temporary improvement in the symptoms. However, this was a severe case of recurrent meningitis and cerebral infarction, sinus thrombosis, and cranial neuropathy, for which sustained improvement was only achieved by additional intrathecal administration of INH.\n\nThere have been only a small number of reports on the use of intrathecal INH. Marked improvement was noted in a case of refractory tuberculous meningitis after thrice-weekly intrathecal administration of 100 mg/day of INH (7). This therapy was also proven to achieve remission in a patient with tuberculous meningitis and liver dysfunction, where the oral administration of high-dose INH was not possible (8). In other reports, two patients were able to return to society without any serious residual effects after combination of intrathecal INH and steroid pulse therapy (9). These findings suggest that intrathecal administration of INH may contribute to an improved prognosis in refractory tuberculous meningitis.\n\nAfter administration, INH rapidly diffuses into the CSF and reaches peak concentrations in excess of 3 mg/L, which is over 30 times its minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis, within 4 hours (10, 11). INH is metabolized in the liver via the N-acetyltransferase 2 (NAT2), which is a polymorphic gene with enzymatic activity that can be altered by the presence of single nucleotide polymorphisms (SNPs) in its coding region (12). Three major genetically determined phenotypes are observed: rapid, intermediate, and slow acetylators (12, 13). Among Brazilian patients with tuberculosis, 72.8% were found to be fast acetylators (14). A meta-analysis showed a significant association between the slow acetylator genotype of NAT2 and antituberculosis drug-induced hepatotoxicity; significant results were also found in East Asians, South Asians, Brazilians, and Middle Eastern populations, but none in Caucasians (15). This implies that the efficacy of INH may be based on NAT2 gene polymorphism and race.\n\nIn our case, the resistance to standard tuberculous therapy and the effectiveness of intrathecal INH were probably due to 1) disturbance of CSF circulation, 2) decline in INH penetration to the focal lesion, and 3) the possibility that the patient was a rapid acetylator of NAT2, although we did not investigate the polymorphism status in the present case. Overall, these findings suggest that refractory tuberculous meningitis or tuberculous meningitis complicated by anti-tuberculosis drug-induced hepatotoxicity may be indications for treatment with intrathecal INH.\n\nThis case exhibited recurrent meningitis symptoms and required administration of corticosteroids over several months. Corticosteroids can improve CSF findings, reduce intracranial pressure, and decrease inflammation (16, 17). It has also been suggested that corticosteroids be routinely used in HIV-negative people with tuberculous meningitis to reduce the risk of death and disabling residual neurologic deﬁcit among survivors (1). Thwaites et al. (6) reported a protocol involving steroid discontinuation after 4 weeks. However, in refractory cases with persistent meningitis symptoms longer than 4 weeks, as exemplified by our patient, we believe that prolonged administration of corticosteroids can be considered.\n\nIn conclusion, multimodal therapy, including intrathecal administration of INH and systemic steroids, should be considered for cases of refractory tuberculous meningitis.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nPrasad K , Singh MB \nCorticosteroids for managing tuberculous meningitis . Cochrane Database Syst Rev \nCD002244 , 2008 .18254003 \n2. \nThwaites G , Fisher M , Hemingway C , Scott G , Solomon T , Innes J , British Infection Society \nBritish Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children . J Infect \n59 : 167 -187 , 2009 .19643501 \n3. \nDastur DK , Manghani DK , Udani PM \nPathology and pathogenetic mechanisms in neurotuberculosis . Radiol Clin North Am \n33 : 733 , 1995 .7610242 \n4. \nWasay M , Farooq S , Khowaja ZA , et al \nCerebral infarction and tuberculoma in central nervous system tuberculosis: frequency and prognostic implications . J Neurol Neurosurg Psychiatry \n85 : 1260 -1264 , 2014 .24623792 \n5. \nHamadeh MA , Glassroth J \nTuberculosis and pregnancy . Chest \n101 : 1114 -1120 , 1992 .1555428 \n6. \nThwaites GE , Nguyen DB , Nguyen HD , et al \nDexamethasone for the treatment of tuberculous meningitis in adolescents and adults . N Engl J Med \n351 : 1741 -1751 , 2004 .15496623 \n7. \nTakahashi T , Ogawa K , Sawada S , et al \nA case of refractory tuberculous meningitis markedly improved by intrathecal administration of isoniazid (INH) . Rinsho Shinkeigaku \n43 : 20 -25 , 2003 (in Japanese, Abstract in English).12820546 \n8. \nDanielides IC , Constantoulakis M , Daikos GK \nHepatitis on high dose isoniazid: reintroduction of the drug in severe tuberculous meningitis . Am J Gastroenterol \n148 : 650 -655 , 1983 .\n9. \nTakahashi I , Yamada M , Matsushima M , et al \nTreatment of intractable tuberculous meningitis using intrathecal isoniazid administration and steroid pulse therapy; a report of two cases . Rinsho Shinkeigaku \n52 : 551 -556 , 2012 (in Japanese, Abstract in English).22975852 \n10. \nThwaites GE , van Toorn R , Schoeman J \nTuberculous meningitis: more questions, still too few answers . Lancet Neurol \n12 : 999 -1010 , 2013 .23972913 \n11. \nEllard GA , Humphries MJ , Allen BW \nCerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis . Am Rev Respir Dis \n148 : 650 -655 , 1993 .8368635 \n12. \nTeixeira RL , Morato RG , Cabello PH \nGenetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients . Mem Inst Oswaldo Cruz \n106 : 716 -724 , 2011 .22012226 \n13. \nKinzig-Schippers M , Tomalik-Scharte D , Jetter A , et al \nShould we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? \nAntimicrob Agents Chemother \n49 : 1733 -1738 , 2005 .15855489 \n14. \nPossuelo LG , Castelan JA , de Brito TC , et al \nAssociation of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil . Eur J Clin Pharmacol \n64 : 673 -681 , 2008 .18421452 \n15. \nDu H , Chen X , Fang Y , et al \nSlow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis . Mol Biol Rep \n40 : 3591 -3596 , 2013 .23277397 \n16. \nFeldman S , Behar AJ , Weber D \nExperimental tuberculous meningitis in rabbits . AMA Arch Pathol \n65 : 343 -354 , 1958 .13507821 \n17. \nParsons M \nTuberculous Meningitis: Tuberculomas and Spinal Tuberculosis: A Handbook for Clinicians . Oxford: Oxford University Press , 1988 : 32 -62 .\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(8)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "cerebral infarction; intrathecal isoniazid; pregnancy; tuberculous meningitis", "medline_ta": "Intern Med", "mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000995:Antitubercular Agents; D044466:Asians; D002544:Cerebral Infarction; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D007278:Injections, Spinal; D007538:Isoniazid; D012008:Recurrence; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal; D014391:Tuberculosis, Miliary", "nlm_unique_id": "9204241", "other_id": null, "pages": "953-957", "pmc": null, "pmid": "28420846", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22975852;1555428;22012226;15496623;18254003;6859018;23277397;12820546;13507821;7610242;15855489;8368635;19643501;24623792;18421452;23972913", "title": "Intrathecal Isoniazid for Refractory Tuberculous Meningitis with Cerebral Infarction.", "title_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction" }

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{ "literaturereference": "NAKATANI Y, SUTO Y, FUKUMA K, YAMAWAKI M, SAKATA R, TAKAHASHI S, NAKAYASU H, NAKASHIMA K. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. 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INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI, Y.. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE. 2017?56:953-957", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200130", "receivedate": "20180112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14381902, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "JP-FRESENIUS KABI-FK201705281", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "19.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200674", "drugbatchnumb": "UNKNOWN", "drugcharacterization": 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"drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091181", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS BACTERIAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Maternal drugs affecting foetus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis tuberculous", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intracranial venous sinus thrombosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Noninfective encephalitis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral artery occlusion", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y,SUTO Y,FUKUMA K,YAMAWAKI M,SAKATA R,TAKAHASHI S,ET AL.. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE 2017;953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170623", "receivedate": "20170623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13681560, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "JP-MITSUBISHI TANABE PHARMA CORPORATION-J201326063", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "209176", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADICUT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201301", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWNDRUG" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "NAKATANI Y,SUTO Y,FUKUMA K,YAMAWAKI M,SAKATA R,TAKAHASHI S,NAKAYASU H,NAKASHIMA K. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERNAL MEDICINE. 2017;56:953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170523", "receivedate": "20170518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13561771, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "JP-MYLANLABS-2017M1036683", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": 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"medicinalproduct": "HEPARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS TUBERCULOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual acuity reduced", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Optic neuropathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NAKATANI Y, SUTO Y, FUKUMA K, YAMAWAKI M, SAKATA R, TAKAHASHI S, ET AL. INTRATHECAL ISONIAZID FOR REFRACTORY TUBERCULOUS MENINGITIS WITH CEREBRAL INFARCTION. INTERN-MED 2017;56(8):953-957.", "literaturereference_normalized": "intrathecal isoniazid for refractory tuberculous meningitis with cerebral infarction", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170620", "receivedate": "20170620", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13669223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "OBJECTIVE\nTo evaluate pegylated interferon alpha2a (PegIFN-alpha2a) in Egyptian patients with HCV genotype 4, and the impact of pretreatment viral load, co-existent bilharziasis and histological liver changes on response rate.\n\n\nMETHODS\nA total of 73 naive patients (61 with history of bilharziasis) with compensated chronic HCV genotype 4 were enrolled into: group A (38 patients) who received 180 mg PegIFN-alpha2a subcutaneously once weekly for a year and group B (35 patients) received IFN alpha-2a 3 MU 3 times weekly. Ribavirin was added to each regimen at a dose of 1200 mg. Patients were followed for 72 wk and sustained response was assessed.\n\n\nRESULTS\nSignificant improvement in both end of treatment response (ETR) (P < 0.002) and sustained response (SR) (P < 0.05) was noted with pegylated interferon, where ETR was achieved in 29 (76.3%) and 14 patients (40%) in both groups respectively, and 25 patients in group A (65.8%) and 9 (25.7%) in group B could retain negative viraemia by the end of follow up period. Sustained virological response (SVR) showed a significant negative correlation with age and positive correlation with pretreatment inflammation in patients receiving PegIFN. Viral clearance after 3 mo of therapy was associated with high incidence of ETR and SR (P < 0.001), but without significant difference between both forms of interferon. Significant improvement in response was achieved in patients with high grade fibrosis (grade 3 and 4) with PegIFN-alpha2a, where SR was seen in 5 out of 13 patients in group A, but none in group B. There was no significant difference in response between bilharzial and non-bilharzial patients in both groups. In terms of safety and tolerability, neutropenia was the predominant side effect; both drugs were comparable.\n\n\nCONCLUSIONS\nPegIFN-alpha2a combined with ribavirin results in improvement in sustained response in HCV genotype 4, irrespective of history of bilharzial infestation.", "affiliations": "Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar. mod2002@qatar-med.cornell.edu", "authors": "Derbala|M F|MF|;Al Kaabi|S R|SR|;El Dweik|N Z|NZ|;Pasic|F|F|;Butt|M T|MT|;Yakoob|R|R|;Al-Marri|A|A|;Amer|A M|AM|;Morad|N|N|;Bener|A|A|", "chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a", "country": "United States", "delete": false, "doi": "10.3748/wjg.v12.i35.5692", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "12(35)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000328:Adult; D000818:Animals; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008099:Liver; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D012547:Schistosoma; D012552:Schistosomiasis; D016896:Treatment Outcome", "nlm_unique_id": "100883448", "other_id": null, "pages": "5692-8", "pmc": null, "pmid": "17007024", "pubdate": "2006-09-21", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": "10895435;10886538;11177692;11757747;11859276;12324553;12515909;12774014;12905138;14679330;14739104;15117320;15479353;8914006;9031902;9670833;15543591;15644127;15888797;15908318;15985008;15990196;10882578;11106716", "title": "Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.", "title_normalized": "treatment of hepatitis c virus genotype 4 with peginterferon alfa 2a impact of bilharziasis and fibrosis stage" }

[ { "companynumb": "QA-ROCHE-1450243", "fulfillexpeditecriteria": "1", "occurcountry": "QA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGINTERFERON ALFA-2A" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MU 3 TIMES WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON ALFA-2A" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thyroid disorder", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DERBALA M, AL KAABI S, EL DWEIK N, PASIC F, BUTT M, YAKOOB R, AL MARRI A, AMER A, MORAD N AND BENER A. TREATMENT OF HEPATITIS C VIRUS GENOTYPE 4 WITH PEGINTERFERON ALFA-2A: IMPACT OF BILHARZIASIS AND FIBROSIS STAGE. WORLD JOURNAL OF GASTROENTEROLOGY : WJG 2006 SEP 21;12(35):5692-5698.", "literaturereference_normalized": "treatment of hepatitis c virus genotype 4 with peginterferon alfa 2a impact of bilharziasis and fibrosis stage", "qualification": "3", "reportercountry": "QA" }, "primarysourcecountry": "QA", "receiptdate": "20140819", "receivedate": "20140819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10392468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Sevelamer is an important drug used to lower serum phosphate levels in advanced kidney disease and in patients on dialysis. This drug is generally well tolerated but some patients report mild gastrointestinal distress as a side effect. Although regulatory agencies, such as Food and Drug Administration, list bowel ischemia and necrosis as potential and rare side effects, there are few case reports describing these adverse effects. We present a 35-year-old HIV patient with end-stage renal disease on hemodialysis who developed colonic hemorrhage and perforation. Imaging showed ischemic gangrene of bowel wall. Histopathology was consistent with transmural ischemic necrosis with deposition of fibrin thrombi and sevelamer crystals.", "affiliations": "Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Internal Medicine, Primary Care, Bellin Health, Marinette, WI, USA.", "authors": "Keri|K C|KC|;Veitla|V|V|;Samji|N S|NS|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/ijn.IJN_80_18", "fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Wolters Kluwer - Medknow India IJN-29-19110.4103/ijn.IJN_80_18Case ReportIschemic Colitis in Association with Sevelamer Crystals Keri K. C. Veitla V. Samji N. S. 1Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA1 Department of Internal Medicine, Primary Care, Bellin Health, Marinette, WI, USAAddress for correspondence: Dr. K. C. Keri, Department of Medicine, Division of Nephrology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: kkeri@mcw.eduMay-Jun 2019 29 3 191 193 Copyright: © 2019 Indian Journal of Nephrology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Sevelamer is an important drug used to lower serum phosphate levels in advanced kidney disease and in patients on dialysis. This drug is generally well tolerated but some patients report mild gastrointestinal distress as a side effect. Although regulatory agencies, such as Food and Drug Administration, list bowel ischemia and necrosis as potential and rare side effects, there are few case reports describing these adverse effects. We present a 35-year-old HIV patient with end-stage renal disease on hemodialysis who developed colonic hemorrhage and perforation. Imaging showed ischemic gangrene of bowel wall. Histopathology was consistent with transmural ischemic necrosis with deposition of fibrin thrombi and sevelamer crystals.\n\nSevelamer associated bowel ischemiasevelamer associated gastrointestinal bleedingsevelamer crystals\n==== Body\nIntroduction\nSevelamer is very commonly used non-calcium-phosphate-binding agent in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients to lower blood phosphate levels.[12] It was first approved for use in 2000. Currently, it is available as sevelamer hydrochloride and sevelamer bicarbonate. Use of this medication has been increasing due to its efficacy with phosphate lowering and the proposed lack of hypercalcemia and associated vascular calcification.[3]\n\nMost commonly reported side effects of sevelamer are noted to be nausea, vomiting, constipation, flatulence, and diarrhea. Although regulatory agencies such as Food and Drug Administration and the drug label list bowel perforation and ischemia as some of the more serious adverse reactions, there is insufficient literature in support of these effects.\n\nIn this case report, we describe a 35-year-old African-American female patient who was treated with sevelamer hydrochloride who presented with acute abdominal pain caused by ischemic colitis and hemorrhage. Biopsy of the right colon tissue revealed fibrinoid necrosis and deposition of crystals, whose description was consistent with sevelamer crystals.\n\nCase Report\nThis is a 35-year African-American female patient with ESRD due to idiopathic focal segmental glomerular sclerosis on hemodialysis. Significant medical history included HIV and seizure disorder. Seizure disorder was been well controlled on phenytoin. HIV status is monitored by HIV clinics at our institution. Her recent CD4 count was within normal limits and the viral load undetectable. Maintenance medication regimen included sevelamer 4.8 g/day, calcitriol, darbepoetin, cholecalciferol, clopidogrel, abacavir, lamivudine, and phenytoin. Notably, she was on sevelamer 1600 md three times a day.\n\nOur patient presented to the hospital with hematochezia, bright red bleeding per rectum and right lower quadrant abdominal pain. At the time of presentation, BP was 114/70, temperature was 98.5°F, and heart rate was 124/min. Blood chemistries were that of an ESRD patient with potassium of 5 mg/dl, serum creatinine of 6.92 mg/dl, and BUN of 41 mg/dl. Contrast CT scan of abdomen and pelvis showed cecal and colon dilatation (15–16 cm), intraluminal hemorrhage, and fat stranding. Lack of bowel wall enhancement was suggestive of ischemic colitis. Due to the above findings, patient underwent exploratory laparotomy and right hemicolectomy which was later followed by ileocolic anastomosis.\n\nThe excised tissue was promptly subjected to pathological analysis. Histopathology of the right colonic tissue showed patchy transmural ischemic necrosis with vascular fibrin thrombi and presence of sevelamer crystals at the necrotic bed and site of perforation [Figures 1 and 2]. These crystals demonstrated broad and curved “fish scale” like morphology. The scales intersected at curved points and displayed a 2-toned pink linear accentuation against a rusty yellow background.\n\nFigure 1 Fibrinoid necrosis (H and E)\n\nFigure 2 Sevelamer crystals displaying broad and curved 2-toned fish scales\n\nDiscussion\nSevelamer is an anion exchanger free of calcium and other metals. This polymeric resin has multiple amines on a carbon backbone. Amines in the polymer exist in a protonated form in the GI tract. Due to their charge, they bind phosphate anion decreasing the overall absorption of phosphorus from the GI tract.[4]\n\nMucosal injury caused by other sequestering agents such as sodium polystyrene sulfate has been reported but little data exist on sevelamer-associated gastrointestinal injury.[567]\n\nSevelamer crystal-associated GI injury was first reported in 2008.[8] In this case report, stercoral ulceration due to fecaloma formation lead to lower intestinal bleeding. The severe constipation was attributed to sevelamer use. However, they did not report sevelamer crystal deposition on histopathology.\n\nIn 2014, Swanson et al. reported a spectrum of GI mucosal injury associated with sevelamer crystal deposition in a case series of 15 patients.[9] Also, the crystal deposition was reported in esophagus, small bowel, and colon. This series described that sevelamer crystals demonstrated broad and curved “fish scale” like morphology. The scales intersected at curved points and displayed a 2-toned pink linear accentuation against a rusty yellow background. They stained eosinophilic to brown on hematoxylin and eosin (H and E) stain and violet on periodic acid-Schiff staining with diastase. To confirm the validity of their findings, they crushed sevelamer tablets and subjected to routine H and E and PAS staining. The crystals in tables demonstrated identical crystal structure to those seen in patient specimens.\n\nSince the publication of this study, there have been reports on sevelamer-associated sigmoidal bleeding,[10] sigmoid colon perforation,[11] and GI mucosal injury causing sigmoid colon mucosal injury with bleeding.[12]\n\nIn our case, the resected bowel was subjected to routine histopathological analysis. Pathology revealed patchy transmural ischemic necrosis [Figure 1] with vascular fibrin thrombi along with sevelamer crystal deposition. The crystals on H and E stained exhibited broad and curved fish scales with two tones against a yellow-brown background. The histopathological description of these crystals is similar to what was described by Swanson et al. Possibility of kayexalate can be raised but the patient had not ingested kayexalate prior around this event. Moreover, kayexalate crystals have narrow rectangular fish scales and are usually exhibit a single color.\n\nDespite visualization of sevelamer crystals at the site of necrosis, the regular causes of bowel ischemia must always be considered. Given the duration of dialysis, vascular calcification and resultant ischemia put these patients at a very high risk of vascular events. Mesenteric ischemia due to invasive fungi throughout the gastrointestinal tract has been reported in dialysis patients.[1314] Another consideration is beta-2 microglobulin amyloidosis. This has been reported to cause ischemic insult throughout the GI tract.[15]\n\nConclusion\nAlthough a rarely described entity, the awareness that sevelamer may be associated with intestinal ischemia is important. However, one must always consider and rule out the common causes of mesenteric ischemia such as atherosclerosis and vascular calcifications along with less common conditions associated with angioinvasive fungal infections and beta-2 microglobulin amyloidosis. More studies are needed to establish if sevelamer is a mere association versus if it causes ischemic injury on its own.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Delmez J Block G Robertson J Chasan-Taber S Blair A Dillon M A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis Clin Nephrol 2007 68 386 91 18184521 \n2 Mathew S Lund RJ Strebeck F Tustison KS Geurs T Hruska KA Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy J Am Soc Nephrol 2007 18 122 30 17182886 \n3 Wang C Liu X Zhou Y Li S Chen Y Wang Y New conclusions regarding comparison of sevelamer and calcium-based phosphate binders in coronary-artery calcification for dialysis patients: A meta-analysis of randomized controlled trials PLoS One 2015 10 e0133938 26230677 \n4 Barna MM Kapoian T O’Mara NB Sevelamer carbonate Ann Pharmacother 2010 44 127 34 19955298 \n5 Lillemoe KD Romolo JL Hamilton SR Pennington LR Burdick JF Williams GM Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: Clinical and experimental support for the hypothesis Surgery 1987 101 267 72 3824154 \n6 Sterns RH Rojas M Bernstein P Chennupati S Ion-exchange resins for the treatment of hyperkalemia: Are they safe and effective? J Am Soc Nephrol 2010 21 733 5 20167700 \n7 Watson M Abbott KC Yuan CM Damned if you do, damned if you don’t: Potassium binding resins in hyperkalemia Clin J Am Soc Nephrol 2010 5 1723 6 20798253 \n8 Madan P Bhayana S Chandra P Hughes JI Lower gastrointestinal bleeding: Association with sevelamer use World J Gastroenterol 2008 14 2615 6 18442219 \n9 Swanson BJ Limketkai BN Liu TC Montgomery E Nazari K Park JY Sevelamer crystals in the gastrointestinal tract (GIT): A new entity associated with mucosal injury Am J Surg Pathol 2013 37 1686 93 24061514 \n10 Subramanian CR GI mucosal injury and bleeding: Association with sevelamer crystals J Gastrointest Dig Syst 2016 12 346 7 \n11 Yamaguchi T Ohyama S Furukawa H Sato N Ohnishi I Kasashima S Sigmoid colon diverticula perforation associated with sevelamer hydrochloride administration: A case report Ann Med Surg (Lond) 2016 10 57 60 27547398 \n12 Chintamaneni P Das R Kuan SF Kermanshahi TR Hashash JG Hematochezia associated with sevalamer-induced mucosal injury ACG Case Rep J 2014 1 145 7 26157856 \n13 Chaudhary A Jain V Dwivedi RS Misra S Invasive aspergillosis causing small bowel infarction in a patient of carcinoma breast undergoing chemotherapy J Carcinog 2006 5 18 16753069 \n14 Lee ZJ Chia C Busmani I Wong WK A rare cause of ischemic gut: A case report Int J Surg Case Rep 2016 20 114 7 26852360 \n15 Dulgheru EC Balos LL Baer AN Gastrointestinal complications of beta2-microglobulin amyloidosis: A case report and review of the literature Arthritis Rheum 2005 53 142 5 15696571\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0971-4065", "issue": "29(3)", "journal": "Indian journal of nephrology", "keywords": "Sevelamer associated bowel ischemia; sevelamer associated gastrointestinal bleeding; sevelamer crystals", "medline_ta": "Indian J Nephrol", "mesh_terms": null, "nlm_unique_id": "8914356", "other_id": null, "pages": "191-193", "pmc": null, "pmid": "31142966", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "15696571;16753069;17182886;18184521;18442219;19955298;20167700;20798253;24061514;26157856;26230677;26852360;27547398;3824154", "title": "Ischemic Colitis in Association with Sevelamer Crystals.", "title_normalized": "ischemic colitis in association with sevelamer crystals" }

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ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS.. 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null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARBEPOETIN ALFA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, 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ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. AMERICAN JOURNAL OF KIDNEY DISEASES. 2018?71(4):554", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190614", "receivedate": "20180501", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14834635, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0098579", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SEVELAMER CARBONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206094", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVELAMER CARBONATE TABLETS, 800 MG" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematochezia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Large intestine perforation", "reactionmeddraversionpt": "21.0", "reactionoutcome": null }, { "reactionmeddrapt": "Abdominal pain lower", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI K, VEITLA V, BAL N, PANT M. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. AM J KIDNEY DIS. 2018?71(4):554.", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180507", "receivedate": "20180507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14852835, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2019GMK041653", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SEVELAMER HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204724", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1600 MG, TID (4.8 G/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1600", "drugstructuredosageunit": "003", 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"activesubstancename": "CALCITRIOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCITRIOL." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Large intestinal haemorrhage", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis ischaemic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Large intestine perforation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KERI KC, VEITLA V, SAMJI NS. ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS.. 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ISCHEMIC COLITIS IN ASSOCIATION WITH SEVELAMER CRYSTALS. INDIAN J NEPHROL. 2019?29(3):191-193", "literaturereference_normalized": "ischemic colitis in association with sevelamer crystals", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190821", "receivedate": "20190821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16726793, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "Association between thymoma and pure red cell aplasia is already well-documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.", "affiliations": "Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.;Azienda Ospedaliero Universitaria San Luigi Gonzaga Università di Torino Orbassano Italy.", "authors": "Dragani|Matteo|M|https://orcid.org/0000-0002-5754-4856;Andreani|Giacomo|G|https://orcid.org/0000-0003-4877-3929;Familiari|Ubaldo|U|;Marci|Valerio|V|;Rege-Cambrin|Giovanna|G|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2642", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2642\nCCR32642\nCase Report\nCase Reports\nPure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory\nDRAGANI et al.Dragani Matteo https://orcid.org/0000-0002-5754-4856\n1\nmatteo.dragani@gmail.com Andreani Giacomo https://orcid.org/0000-0003-4877-3929\n1\n Familiari Ubaldo \n1\n Marci Valerio \n1\n Rege‐Cambrin Giovanna \n1\n \n1 \nAzienda Ospedaliero Universitaria San Luigi Gonzaga\nUniversità di Torino\nOrbassano\nItaly\n\n* Correspondence\n\nMatteo Dragani, Hematology Department, San Luigi Gonzaga Hospital, University of Turin, Orbassano 10123, Italy.\n\nEmail: matteo.dragani@gmail.com\n\n17 3 2020 \n4 2020 \n8 4 10.1002/ccr3.v8.4598 601\n22 4 2019 09 10 2019 10 10 2019 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAssociation between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.\n\nAssociation between thymoma and pure red cell aplasia is already well‐documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.\n\n\namegakaryocytic thrombocytopeniaaplasiaeltrombopagT‐cell immunitythymoma source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:08.04.2020\n\n\nDragani \nM \n, \nAndreani \nG \n, \nFamiliari \nU \n, \nMarci \nV \n, \nRege‐Cambrin \nG \n. Pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory\n. Clin Case Rep . 2020 ;8 :598 –601\n. 10.1002/ccr3.2642\n==== Body\n1 CASE PRESENTATION\nA 62‐year‐old male was first diagnosed with lymphocyte‐rich thymoma in 2014 after being admitted in the emergency ward for sudden dyspnea and deep vein thrombosis of the right arm. His past medical history was uneventful, and he was nonsmoker. Notably, his blood examinations were perfectly normal. In June 2014, he was administered five cycles of chemotherapy based on standard CAPP (cisplatin, doxorubicin, cyclophosphamide, and prednisone) regimen obtaining a partial response.\n\nFrom 2014 to 2017, the disease remained stable; in May 2017, the tumor burden increased with enlargement of the main mediastinal lesion and metastasis localized to the pleura, the diaphragm, and the second rib. In June 2017, the oncologist picked the CAPP regimen for a rechallenge but only one course of chemo was administered due to the appearance of normocytic anemia (Hb, 7 g/dL). At first, erythropoietin was prescribed but it did not show any effect.\n\nThe patient was refereed to our hematology department for further investigation. His anemia was not carential, not due to blood loss, not hemolytic, so prescription of erythropoiesis‐stimulating factor to contain chemotherapy‐induced anemia can be of help. Differential diagnosis includes performing a bone marrow biopsy to exclude therapy‐related myelodysplasia which can impair blood count recovery and led to aggressive forms of acute myeloid leukemia.\n\nIn July 2017, while the patient already has been put under blood transfusion weekly, a bone marrow biopsy was done, and it showed pure red cell aplasia (PRCA) with normal granulocyte maturation and megakaryocytes representation and a global cellularity around 50%. No cytogenetic abnormalities associated with myelodysplasia could be detected with FISH analysis, and remarkably no sign of thymoma metastasis in the marrow had been noticed. Blood count was as follows: WBC, 5900/μL; Hb, 6.5 g/dL; and platelets 327 000/μL.\n\nThymoma is the most common neoplastic lesion of the anterior mediastinum whose paraneoplastic complications such as myasthenia gravis (MG) and pure red cell aplasia (PRCA) are well‐known. About 25%‐30% of patients with thymoma experiences MG whereas approximately 2%‐5% of thymoma patients have pure red cell aplasia1 with the possibility of achieving complete remission of the latter after cyclosporine‐based immunosuppressive therapy, especially if total thymectomy is performed.\n\nIn August 2017, the patient developed severe thrombocytopenia with mucocutaneous bleeding (platelets: 14 000/μL). A second bone marrow biopsy was done exactly one month after the first one, and it showed pure red aplasia with amegakaryocytic thrombocytopenia (Figure 1). Cellularity was about 30% with normal granulocyte representation. Notably, no myeloid blasts were detected; WT1 rate was 20 and cytogenetic testing showed no abnormalities.\n\nFigure 1 Bone marrow in July 2017 with absence of erythroid precursors, normal granulocytic, and megakaryocytic representation, cellularity around 50% (left); bone marrow in August 2017 with absence of both erythroid and megakaryocytic precursors, cellularity around 30% (right)\n\nThe development of severe thrombocytopenia just one month after the first biopsy where megakaryopoiesis showed no sign of impairment was unexpected. Patients with thymoma can experience thrombocytopenia in the context of aplastic anemia or immune thrombocytopenic purpura; in this case, aplastic anemia was ruled out due to the presence of 30% of cellularity with no sign of granulocytes’ alterations; immune thrombocytopenic purpura was excluded because it is associated with normal or increased megakaryocytes as a compensatory mechanism.\n\nAfter August 2017, the patient was both red blood cell and platelets transfusion‐dependent. Combination therapy with cyclosporine 3 mg/kg, prednisone 50 mg/die, and dose‐escalation eltrombopag until the maximum dosage of 150 mg/die was promptly initiated with the addition of deferasirox as iron chelator. Four months of this combination therapy, from October 2017 to January 2018, did not provide any benefit.\n\nThe idea behind this therapy was that this step‐by‐step cytopenia could benefit by the combination of immunosuppression with a stimulating agent like eltrombopag, plus the addition of deferasirox which in some hematological malignancies has been able to cause erythroid response.2 Complete resection of the tumor was ruled out because of the metastasis and lack of a clear cleavage plan of the main lesion. Another course of chemotherapy was taken into consideration but excluded at the end to not further impair patient's performance status and to not risk pancytopenia and neutropenic fever.\n\nAt the end of January, for the first time a neutrophil count < 1.000/uL was observed. During these months of immunosuppressive therapy, thymoma remained stable but the patient was admitted twice in the emergency ward for sepsis. When the PRCA plus AT progressed to overt severe aplastic anemia, we interrupted eltrombopag and admitted the patients into the intensive hematological care unit to try a course of horse antithymocyte globulin (ATG) plus cyclosporine and high dose of steroids. Bone marrow transplantation from matched unrelated donor was taken into consideration as a salvage plan if the blood count would have shown no response to T‐lymphocyte depletion. Unfortunately, the patient died just before the ATG administration for a massive intracranial hemorrhage, despite multiple platelet transfusions and careful management of his blood pressure.\n\n2 DISCUSSION\nOnly six patients have been reported in literature to have thymoma associated with pure red cell aplasia and amegakaryocytic thrombocytopenia (Table 1) with, as shown, different bone marrow characteristics and experiencing different oncologic management, from complete resection at first to standard chemotherapy (which includes cyclophosphamide, cisplatin, steroids, and doxorubicin).\n\nTable 1 Case reports available on PubMed\n\nReports\tSex/Age\tBM Evaluation\tPRCA—AT timeline\tThymoma history\t\nMaslovsky (2005)\tM, 41 y\tPure red cell aplasia, absence of megakaryocytes, normal maturation and differentiation of myeloid precursors\tPRCA first followed by AT after 3 mo\tThymoma diagnosed with PRCA; AT occurred after partial tumor resection and chemo.\t\nSimkins (2017)\tF, 61 y\tBM cellularity 40%, erythroid and megakaryocytic aplasia with left‐shifted myeloid maturation\tPRCA and AT at the same time\tLymphocyte‐rich thymoma, CAPP chemotherapy, radical thymectomy performed before PRCA and AT\t\nDahal (2018)\tM, 60 y\tBM hypercellular with severely depleted megakaryocytes and erythroid precursor cells and relative myeloid hyperplasia\tPRCA and AT at the same time\tRecurrent invasive thymoma, no surgery ever performed, diagnosis made before PRCA and AT\t\nOnuki (2016)\tF, 67 y\tBM hypoplastic, decreased erythroid cells, scarce megakaryocytes, adequate number of myeloid cells\tPRCA and AT at the same time\tThymoma occurred at presentation with PRCA and AT\t\nGay (2014)\tM, 31 y\tBM cellularity 20%, erythroid precursors 1%, markedly reduced to absent megakaryocytes\tPRCA and AT at the same time\tRelapsed thymoma after complete resection; PRCA and AT diagnosed after CAPP chemotherapy and partial remission\t\nFujiwara (2015)\tF, 44 y\tBM hypocellular with marked decrease in megakaryocytes and reticulocytes\tPRCA first followed by AT (no time frame available)\tRefractory thymoma diagnosed with PRCA, AT occurred after CAPP‐like chemotherapy and II line treatment with CAMP regimen\t\nPresent case (2018)\tM, 62 y\tBM cellularity 30%, normal granulocyte maturation, no evidence of erythroid and megakaryocytic precursors\tPRCA first followed by AT after 1 mo\tRefractory thymoma; no surgery ever performed; PRCA and then AT occurred after chemotherapy (first CAPP course, then rechallenge two years later).\t\nFeatures of bone marrow, time frame of PRCA (pure red cell aplasia) and AT (amegakaryocytic thrombocytopenia) occurrence, and history of thymoma are shown.\n\nJohn Wiley & Sons, LtdTreatment in this series of patient always included cyclosporine backbone, alone or in combination with prednisone, and in two cases also horse ATG were administered. Eltrombopag has been used, beside our patient, in only one case but no improvement of platelet count was obtained; at the end a bone marrow, transplant from matched unrelated donor was successfully performed.3 Our case is an example where the addition of a TPO agonist did not provide an hematological recovery, whereas in the latest years this molecule has been proven effective in the treatment of severe aplastic anemia (SAA) both as a single agent in SAA refractory to IST or in frontline combination with cyclosporine/horse ATG.4, 5\n\n\nBetween these cases, four patients were able to improve their cytopenias6, 7, 8, 9 whereas in the remaining two cases information about follow‐up were not available and one patient left the hospital few days after therapy initiation.9, 10 Notably, in three cases including ours PRCA and amegakaryocytic thrombocytopenia (AT) progressed to aplastic anemia despite immunosuppression, thus empowering the theory, previously cited in the other reports, that PRCA and AT may be early presentation of complete aplasia.\n\nOur impression is that patients with PRCA and AT with thymoma have better chances to achieve hematological improvement of their cytopenias if complete resection of the tumor can be performed at some point. Previous experiences indicate that both humoral and T cell–mediated immunity can be accounted as culprits of megakaryocytes suppression, and since thymomas can dysregulate both pathways we may assume that the presence of the tumor can overcome the effects of immunosuppressive therapy.11, 12 Nevertheless, certainties in this particular field are very scarce since thymoma itself is a rare entity and the discussion can only rely on sporadic experiences: further reports are needed as well as prospective studies to determine the role of eltrombopag, bone marrow transplantation, and surgical resection of the tumor.\n\nCONFLICTS OF INTEREST\nThe authors declare no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\nMD, GRC, and GA: treated the patient. VM and UF performed the histological analysis. MD, GRC, and GA: wrote the paper.\n==== Refs\nREFERENCES\n1 \n\nChintakuntlawar \nAV \n, \nRizvi \nSA \n, \nCassivi \nSD \n, \nPardanani \nA \n. Thymoma associated pancytopenia: immunosuppressive therapy is the cornerstone for durable hematological remission\n. Ann Hematol . 2015 ;94 :453 .25315166 \n2 \n\nCilloni \nD \n, \nBiale \nL \n, \nCapelli \nD \n et al. Feasibility and efficacy of combined treatment with eltrombopag and deferasirox in patients affected by aplastic anemia\n. EHA Library . 2018 ;216392 ;abstract PB1823.\n3 \n\nMaslovsky \nI \n, \nGefel \nD \n, \nUriev \nL \n, \nBen Dor \nD \n, \nLugassy \nG \n. Malignant thymoma complicated by amegakaryocytic thrombocytopenic purpura\n. Eur J Intern Med . 2005 ;16 :523 ‐524\n.16275552 \n4 \n\nScheinberg \nP \n. Activity of Eltrombopag in severe aplastic anemia\n. Blood Adv . 2018 ;2 (21 ):3054 ‐3062\n.30425070 \n5 \n\nTownsley \nDM \n, \nScheinberg \nP \n, \nWinkler \nT \n, et al. Eltrombopag added to standard immunosuppression for aplastic anemia\n. 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Thymoma complicated by acquired amegakaryocytic thrombocytopenia and pure red cell aplasia\n. J Natl Compr Canc Netw . 2014 ;12 (11 ):1505 ‐1509\n.25361796 \n10 \n\nDahal \nS \n, \nSharma \nE \n, \nDahal \nS \n, \nShrestha \nB \n, \nBhattarai \nB \n. al ‐ Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia in thymoma\n. Case Rep Hematol . 2018 ;2018 :1 ‐3\n.\n11 \n\nBenedetti \nF \n, \nde Sabata \nD \n, \nPerona \nG \n. T suppressor activated lymphocytes (CD8+/DR+) inhibit megakaryocyte progenitor cell differentiation in a case of acquired amegakaryocytic thrombocytopenic purpura\n. Stem Cells . 1994 ;12 (2 ):205 ‐213\n.8199563 \n12 \n\nKuwaki \nT \n, \nHagiwara \nT \n, \nKato \nT \n, \nMiyazaki \nH \n. Auto antibodies neutralizing thrombopoietin in a patient with amegakaryocytic thrombocytopenic purpura\n. Blood . 2000 ;95 (6 ):2187 ‐2188\n.10755821\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(4)", "journal": "Clinical case reports", "keywords": "T‐cell immunity; amegakaryocytic thrombocytopenia; aplasia; eltrombopag; thymoma", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "598-601", "pmc": null, "pmid": "32274018", "pubdate": "2020-04", "publication_types": "D002363:Case Reports", "references": "29409729;28423296;28053696;10755821;29713553;30425070;25361796;25555981;25315166;8199563;16275552", "title": "Pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma: The uncharted territory.", "title_normalized": "pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma the uncharted territory" }

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PURE RED CELL APLASIA AND AMEGAKARYOCYTIC THROMBOCYTOPENIA IN THYMOMA: THE UNCHARTED TERRITORY. CLINICAL CASE REPORTS. 2020?8(4):598-601", "literaturereference_normalized": "pure red cell aplasia and amegakaryocytic thrombocytopenia in thymoma the uncharted territory", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200508", "receivedate": "20200506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17750851, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]

{ "abstract": "Neurotoxic manifestations due to chronic metronidazole intake are well known, but neurotoxicity due to short-term use of metronidazole is very rare. We present a case of acute neurotoxicity due to short course of injectable metronidazole given in usual doses to a renal allograft recipient for persistent diarrhea. It responded to withdrawal of the offending drug. Tacrolimus trough concentration did not increase during neurotoxicity, thereby ruling out any metronidazole-tacrolimus interaction. Magnetic resonance imaging of the brain showed widespread osmotic demyelination and its recovery after drug withdrawal. This is the first reported case of a renal transplant recipient developing acute neurotoxicity due to short-term use of metronidazole, without any increase in tacrolimus trough concentrations.", "affiliations": "Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.", "authors": "Dogra|Pavitra Manu|PM|;Bhatt|Anil Kumar|AK|;Agarwal|Sanjay Kumar|SK|;Bhowmik|Dipankar|D|", "chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D008795:Metronidazole; D016559:Tacrolimus", "country": "Saudi Arabia", "delete": false, "doi": "10.4103/1319-2442.248315", "fulltext": null, "fulltext_license": null, "issn_linking": "1319-2442", "issue": "29(6)", "journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia", "keywords": null, "medline_ta": "Saudi J Kidney Dis Transpl", "mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D003967:Diarrhea; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008795:Metronidazole; D017590:Myelinolysis, Central Pontine; D016559:Tacrolimus; D016896:Treatment Outcome", "nlm_unique_id": "9436968", "other_id": null, "pages": "1511-1514", "pmc": null, "pmid": "30588989", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": null, "title": "Short-course metronidazole-induced reversible acute neurotoxicity in a renal transplant recipient.", "title_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient" }

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SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. 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"1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurological examination abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA P, BHATT A, AGARWAL S, BHOWMIK D. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. 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"patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Osmotic demyelination syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT. SAUDI J KIDNEY DIS TRANSPL. 2018 NOV-DEC?29(6):1511-1514.", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20191122", "receivedate": "20191122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17063189, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "IN-STRIDES ARCOLAB LIMITED-2019SP000082", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebellar ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Clumsiness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Extensor plantar response", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Movement disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Speech disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D.. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT.. SAUDI-J-KIDNEY-DIS-TRANSPL. 2018?29(6):1511-1514", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15797050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "IN-GLENMARK PHARMACEUTICALS-2019GMK044380", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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"drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osmotic demyelination syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DOGRA PM, BHATT AK, AGARWAL SK, BHOWMIK D.. SHORT-COURSE METRONIDAZOLE-INDUCED REVERSIBLE ACUTE NEUROTOXICITY IN A RENAL TRANSPLANT RECIPIENT.. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION: AN OFFICIAL PUBLICATION OF. 2018?29(6):1511-1514", "literaturereference_normalized": "short course metronidazole induced reversible acute neurotoxicity in a renal transplant recipient", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20191125", "receivedate": "20191125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17070383, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "There is limited information about the prevalence and treatment of concurrent acetaminophen and iron overdose. One case study has suggested that this combination may be lethal. We present a case of fatal intentional acetaminophen and iron overdose and treatment with extracorporeal methods, including continuous venovenous hemofiltration and plasmapheresis, for removal of both toxins.", "affiliations": "Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, USA.;Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, USA.", "authors": "Nye|Rebecca|R|;Singh|Tripti|T|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000517231", "fulltext": null, "fulltext_license": null, "issn_linking": "0253-5068", "issue": null, "journal": "Blood purification", "keywords": "Acetaminophen; Continuous renal replacement therapy; Iron; Overdose; Plasmapheresis", "medline_ta": "Blood Purif", "mesh_terms": null, "nlm_unique_id": "8402040", "other_id": null, "pages": "1-4", "pmc": null, "pmid": "34237719", "pubdate": "2021-07-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Use of CRRT and Plasmapheresis to Treat Simultaneous Iron and Acetaminophen Overdose.", "title_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose" }

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Use of CRRT and Plasmapheresis to Treat Simultaneous Iron and Acetaminophen Overdose.. 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USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIF. 2021?8:UNK?UNK. 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USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIF. 2021?1?4. 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USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. 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null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INTENTIONAL OVERDOSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHARCOAL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PHENYLEPHRINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUOUS INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYLEPHRINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VASOPRESSIN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONTINUOUS INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VASOPRESSIN." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH T. USE OF CRRT AND PLASMAPHERESIS TO TREAT SIMULTANEOUS IRON AND ACETAMINOPHEN OVERDOSE. BLOOD PURIFICATION. 2021 JUL 08?.", "literaturereference_normalized": "use of crrt and plasmapheresis to treat simultaneous iron and acetaminophen overdose", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210916", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19816181, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty-four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].", "affiliations": "Children's Healthcare of Atlanta, Atlanta, GA, USA.;University of North Carolina Health Care, Chapel Hill, NC, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.;Division of Pediatric Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.", "authors": "Bernardo|Valeria|V|0000-0003-4338-1184;Miles|Alyssa|A|;Fernandez|Alfred J|AJ|;Liverman|Rochelle|R|;Tippett|Ashley|A|;Yildirim|Inci|I|0000-0002-8631-0020", "chemical_list": "D000935:Antifungal Agents; D003692:Delayed-Action Preparations; D013607:Tablets; D014230:Triazoles; C101425:posaconazole", "country": "Denmark", "delete": false, "doi": "10.1111/petr.13777", "fulltext": null, "fulltext_license": null, "issn_linking": "1397-3142", "issue": "24(6)", "journal": "Pediatric transplantation", "keywords": "fungal infection; pediatrics; posaconazole; therapeutic level", "medline_ta": "Pediatr Transplant", "mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000935:Antifungal Agents; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D016867:Immunocompromised Host; D007262:Infusions, Intravenous; D000072742:Invasive Fungal Infections; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D013607:Tablets; D016896:Treatment Outcome; D014230:Triazoles; D055815:Young Adult", "nlm_unique_id": "9802574", "other_id": null, "pages": "e13777", "pmc": null, "pmid": "32639095", "pubdate": "2020-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.", "title_normalized": "initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children adolescents and young adults receiving delayed release tablet and intravenous posaconazole" }

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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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INITIAL POSACONAZOLE DOSING TO ACHIEVE THERAPEUTIC SERUM POSACONAZOLE CONCENTRATIONS AMONG CHILDREN, ADOLESCENTS, AND YOUNG ADULTS RECEIVING DELAYED?RELEASE TABLET AND INTRAVENOUS POSACONAZOLE. 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{ "abstract": "Immunotherapy has been in use for the treatment of melanoma since a very long time, but only recently have the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab and programmed cell death-1 inhibitors such as nivolimumab and pembrolizumab been shown to induce marked improvements in survival in patients with metastatic melanoma. An important concern arises in terms of the safety of the use of these agents in patients with autoimmune diseases, solid organ transplant recipients on immunosuppression, patients with a history of previous hepatitis B or C, and patients with HIV infections as these patients were excluded from pivotal immunotherapy studies. Here, we report on the safety and efficacy of pembrolizumab in a melanoma patient with multiple medical problems including poorly controlled rheumatoid arthritis and we review the available literature on the use of immunotherapy and autoimmune diseases. The weight of evidence suggests that these patients should be offered the opportunity to benefit from immune check point inhibitors, with drugs targeting programmed cell death-1 being preferred. More research is required to study the long-term effects of immunotherapy on patients with autoimmune diseases.", "affiliations": "aDepartment of Internal Medicine, Banner University Medical Center, Phoenix bDepartment of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, Arizona.", "authors": "Puri|Akshjot|A|;Homsi|Jade|J|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab", "country": "England", "delete": false, "doi": "10.1097/CMR.0000000000000387", "fulltext": null, "fulltext_license": null, "issn_linking": "0960-8931", "issue": "27(5)", "journal": "Melanoma research", "keywords": null, "medline_ta": "Melanoma Res", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma; D012878:Skin Neoplasms", "nlm_unique_id": "9109623", "other_id": null, "pages": "519-523", "pmc": null, "pmid": "28817445", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis.", "title_normalized": "the safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis" }

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{ "abstract": "The number of cases of coronavirus disease 2019 (COVID-19) has been exponentially increasing everyday. It is important to recognize the comorbidities and risk factors associated with this highly contagious and serious disease that has caused thousands of deaths worldwide. Patients with certain conditions like diabetes, hypertension, cardiovascular disease and chronic lung diseases have been reported to develop serious complications from COVID-19. Idiopathic pulmonary fibrosis (IPF) is a disease that is more prevalent in the elderly population, the same group that are more susceptible to serious complications from COVID-19. Our literature search did not reveal any review about COVID-19 in IPF patients. We report a patient with IPF who was exposed to COVID-19 from her spouse and died from its complications. This case would help to raise the awareness among IPF patients to follow the necessary precautions to reduce the risk of contracting the disease.", "affiliations": "Pulmonary Critical Care, Novant Health, Winston-Salem, USA.;Pulmonary Critical Care, Yale New Haven Health at Bridgeport Hospital, Bridgeport, USA.;Hematology and Oncology, Decatur Memorial Hospital, Decatur, USA.;Cardiology, Decatur Memorial Hospital, Decatur, USA.", "authors": "Rajasurya|Venkat|V|;Gunasekaran|Kulothungan|K|;Damarla|Vijay|V|;Kolluru|Anuradha|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.8432", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8432\nInternal Medicine\nInfectious Disease\nPulmonology\nA Fatal Case of Coronavirus Disease 2019 (COVID-19) in a Patient With Idiopathic Pulmonary Fibrosis\nMuacevic Alexander Adler John R Rajasurya Venkat 1 Gunasekaran Kulothungan 2 Damarla Vijay 3 Kolluru Anuradha 4 \n1 \nPulmonary Critical Care, Novant Health, Winston-Salem, USA \n\n2 \nPulmonary Critical Care, Yale New Haven Health at Bridgeport Hospital, Bridgeport, USA \n\n3 \nHematology and Oncology, Decatur Memorial Hospital, Decatur, USA \n\n4 \nCardiology, Decatur Memorial Hospital, Decatur, USA \n\nVenkat Rajasurya vrajasurya@gmail.com\n3 6 2020 \n6 2020 \n12 6 e843218 5 2020 3 6 2020 Copyright © 2020, Rajasurya et al.2020Rajasurya et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/33449-a-fatal-case-of-coronavirus-disease-2019-covid-19-in-a-patient-with-idiopathic-pulmonary-fibrosisThe number of cases of coronavirus disease 2019 (COVID-19) has been exponentially increasing everyday. It is important to recognize the comorbidities and risk factors associated with this highly contagious and serious disease that has caused thousands of deaths worldwide. Patients with certain conditions like diabetes, hypertension, cardiovascular disease and chronic lung diseases have been reported to develop serious complications from COVID-19. Idiopathic pulmonary fibrosis (IPF) is a disease that is more prevalent in the elderly population, the same group that are more susceptible to serious complications from COVID-19. Our literature search did not reveal any review about COVID-19 in IPF patients. We report a patient with IPF who was exposed to COVID-19 from her spouse and died from its complications. This case would help to raise the awareness among IPF patients to follow the necessary precautions to reduce the risk of contracting the disease.\n\ncovid-19corona virusipfidiopathic pulmonary fibrosisacute hypoxemic respiratory failureThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nCoronavirus disease 2019 (COVID-19) is a rapidly spreading infectious disease caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1]. This pandemic has already led to thousands of deaths worldwide, and the number of infected cases continues to rise everyday. Although this virus could infect anyone, it has been found that patients who are older and those with certain pre-existing comorbidities suffer from serious complications due to this disease. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown etiology and its prevalence is higher in the elderly population. Chronic lung disease has been recognized as a risk factor for serious COVID-19 disease, and we report a case of fatal COVID-19 viral pneumonia in a patient with IPF [1-3]. \n\nCase presentation\nOn April 2, 2020, a 79-year-old female with a history of hypertension and IPF presented with cough, worsening dyspnea, increased oxygen requirements, fever and diarrhea. Her vital signs include a temperature of 100.4°F, a heart rate of 98 bpm, an oxygen saturation of 85% on room air and a blood pressure of 102/56 mmHg. She is usually on oxygen two liters per minute at home for chronic hypoxic respiratory failure from IPF. She was on nintedanib 100 mg twice daily for her IPF and metoprolol 12.5 mg daily for her hypertension. Her pulmonary function test done two years ago showed moderate restrictive lung disease with a forced vital capacity of two liters (77% predicted), total lung capacity of three liters (63% predicted) and diffusion capacity of 58% predicted. Her physical exam was unremarkable. She was placed on isolation precautions because of her clinical presentation and her test for SARS-CoV-2 came back positive (Roche’s Cobas nucleic acid amplification test). She was exposed to her husband who was recently diagnosed with COVID-19. She required three liters of supplemental oxygen for her hypoxemia. Chest radiology showed multifocal consolidations in both lungs (Figure 1).\n\nFigure 1 Chest X-ray\n(A) Chest X-ray done three months prior to presentation shows bilateral interstitial infiltrates predominantly in the lung bases. (B) Chest X-ray done on day 4 of COVID-19 shows worsening bilateral multifocal infiltrates superimposed on chronic changes.\n\nShe received azithromycin and hydroxychloroquine as per the protocol. However, her condition deteriorated requiring 10 liters of supplemental oxygen and on day 3 she was transferred to intensive care unit and intubated for worsening hypoxic respiratory failure. She required 100% fractional concentration of oxygen in inspired gas (FiO2) and 10 cm H2O positive end-expiratory pressure (PEEP) on the ventilator. A limited bedside echocardiogram revealed normal left and right ventricular function. Her inflammatory markers continued to worsen. Ferritin which was 600 ng/mL at the time of her presentation, worsened to 50,480 ng/mL. Her white blood cell (WBC) count was 15,000/mm3 with an absolute lymphocyte count of 800/mm3, procalcitonin was 0.14 ng/mL, D-dimer was 3.3 µg/mL and lactate dehydrogenase (LDH) was 628 IU/L. She received a single intravenous dose of tocilizumab 600 mg. On day 4, she developed severe septic shock and multiorgan dysfunction (worsening renal function, liver function, circulatory collapse and respiratory failure) requiring norepinephrine, vasopressin, phenylephrine and angiotensin II. She was started on intravenous hydrocortisone 100 mg three times daily, but despite all the aggressive measures she died on day 5. We would like to mention that at the time of this patient's presentation, other treatments like convalescent plasma and remdesivir were not readily available. \n\nDiscussion\nChronic lung disease has been reported as a potential risk factor for COVID-19 caused by SARS-CoV-2. In a study that looked at the clinical characteristics and comorbidities in more than 44,000 patients infected with SARS-CoV-2 in China, chronic lung disease had been listed as a comorbidity in only 2.4% of them [1]. On April 8 2020, Centers for Disease Control (CDC) released an early report on the characteristics of hospitalized patients with COVID-19 in the United States, and chronic lung disease was reported as a risk factor in 34.6% of the 159 hospitalized COVID-19 patients [2]. It was also reported that 80% of these patients had obstructive lung disease. On April 29 2020, in the data released by CDC, out of 305 COVID-19 patients in Georgia, chronic respiratory disease was reported as a comorbidity in 20.3% and out of whom 77% had obstructive airway diseases [3]. The prevalence of COVID-19 in IPF has not been reported. IPF is the most common type of idiopathic interstitial pneumonia, characterized by progressive fibrosis with a high fatality rate. The incidence and prevalence of the disease increase with age. IPF is characterized by inflammation and lung injury, and the role of cytokines in its pathogenesis has been well established [4]. There is accumulating evidence that a subgroup of patients with COVID-19 develop cytokine storm syndrome leading to increased mortality from the virus-induced hyperinflammation [5]. It is possible that co-existence of these two fatal disease conditions may significantly affect patient outcomes. On the other hand, survivors of COVID 19 have been reported to develop pulmonary fibrosis as a consequence of dysregulated immune response [6].\n\nConclusions\nPatients living with IPF may not be at increased risk for contracting COVID-19, but probably are at high risk for developing severe fatal complications from the disease. Hence, it is vital to recognize IPF as a potential serious risk factor for COVID-19 complications and IPF patients take the necessary extra precautions advised by CDC to protect themselves and minimize the risk of contracting COVID-19.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet Huang C Wang Y Li X 497 506 395 2020 31986264 \n2 Centers for Disease Control and Prevention: COVID-19 Response Team. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 States, March 1-30 5 2020 2020 https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6915e3-H.pdf \n3 Centers for Disease Control and Prevention: COVID-19 Response Team. Characteristics and clinical outcomes of adult patients hospitalized with COVID-19 - Georgia March 5 2020 2020 https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6918e1-H.pdf \n4 The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis Antioxid Redox Signal Bringardner BD Baran CP Eubank TD Marsh CB 287 302 10 2008 17961066 \n5 COVID- 19: consider cytokine storm syndromes and immunosuppression Lancet Mehta P McAuley DF Brown M 1033 1034 395 2020 32192578 \n6 Advances in the research of mechanism of pulmonary fibrosis induced by Corona Virus Disease 2019 and the corresponding therapeutic measures. [Article in Chinese] Zhonghua Shao Shang Za Zhi Wang J Wang BJ Yang JC 0 36 2020\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(6)", "journal": "Cureus", "keywords": "acute hypoxemic respiratory failure; corona virus; covid-19; idiopathic pulmonary fibrosis; ipf", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e8432", "pmc": null, "pmid": "32642347", "pubdate": "2020-06-03", "publication_types": "D002363:Case Reports", "references": "32298251;17961066;32174095;31986264;32192578", "title": "A Fatal Case of Coronavirus Disease 2019 (COVID-19) in a Patient With Idiopathic Pulmonary Fibrosis.", "title_normalized": "a fatal case of coronavirus disease 2019 covid 19 in a patient with idiopathic pulmonary fibrosis" }

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{ "abstract": "OBJECTIVE\nThe physiological interaction between the intrathecal baclofen (ITB) delivery system and the ventriculoperitoneal (VP) shunting system in a patient who had both systems implanted has not been reported previously. The aim of our report is to evaluate the effect that one system's infection might have on the other.\n\n\nMETHODS\nRecords of children who were followed at our institution between 2004 and 2015 for management of their ITB systems were reviewed. In this group, children who had VP shunts were identified, and those who had any of their ITB or VP systems infected were included.\n\n\nRESULTS\nOut of 313 children managed with ITB therapy at our institution, 31 (24%) children had VP shunts. Two patients had infection in both systems, and 3 patients had infection in 1 system.\n\n\nCONCLUSIONS\nThis report suggests that if aspiration from both systems showed positive cultures, the treatment would be removal of both systems. If the primarily not infected system does not show positive cultures, it does not need to be removed. Close follow-up is recommended, and any sign of infection or malfunction of the primarily not infected device should be approached with a high level of suspicion.", "affiliations": "Department of Orthopaedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.", "authors": "Abousamra|Oussama|O|;Duque Orozco|Maria Del Pilar|MDP|;Rogers|Kenneth J|KJ|;Miller|Freeman|F|;Sees|Julieanne P|JP|", "chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen", "country": "Switzerland", "delete": false, "doi": "10.1159/000475468", "fulltext": null, "fulltext_license": null, "issn_linking": "1016-2291", "issue": "53(1)", "journal": "Pediatric neurosurgery", "keywords": "Infection; Intrathecal baclofen; Spasticity; Ventriculoperitoneal shunt", "medline_ta": "Pediatr Neurosurg", "mesh_terms": "D000293:Adolescent; D001418:Baclofen; D002648:Child; D002675:Child, Preschool; D004866:Equipment Contamination; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central; D017287:Ventriculoperitoneal Shunt; D055815:Young Adult", "nlm_unique_id": "9114967", "other_id": null, "pages": "1-6", "pmc": null, "pmid": "28866663", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": null, "title": "Infections of Intrathecal Baclofen Delivery Systems and Ventriculoperitoneal Shunting Systems: Clinical Series Discussion.", "title_normalized": "infections of intrathecal baclofen delivery systems and ventriculoperitoneal shunting systems clinical series discussion" }

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{ "abstract": "Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment.", "affiliations": "Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan.", "authors": "Iizumi|Sakura|S|;Shimoi|Tatsunori|T|;Nishikawa|Tadaaki|T|;Kitano|Atsuko|A|;Sasada|Shinsuke|S|;Shimomura|Akihiko|A|;Noguchi|Emi|E|;Yunokawa|Mayu|M|;Yonemori|Kan|K|;Shimizu|Chikako|C|;Fujiwara|Yasuhiro|Y|;Tamura|Kenji|K|", "chemical_list": "D050071:Bone Density Conservation Agents; D014807:Vitamin D; D000069448:Denosumab; D002118:Calcium", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8908-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894357410.2169/internalmedicine.8908-17Case ReportProlonged Hypocalcemia Following a Single Dose of Denosumab for Diffuse Bone Metastasis of Gastric Cancer after Total Gastrectomy Iizumi Sakura 1Shimoi Tatsunori 1Nishikawa Tadaaki 1Kitano Atsuko 1Sasada Shinsuke 2Shimomura Akihiko 1Noguchi Emi 1Yunokawa Mayu 1Yonemori Kan 1Shimizu Chikako 1Fujiwara Yasuhiro 1Tamura Kenji 1\n1 Department of Breast and Medical Oncology, National Cancer Center Hospital, Japan\n2 Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, JapanCorrespondence to Dr.　Tatsunori Shimoi, tshimoi@ncc.go.jp\n\n25 9 2017 1 11 2017 56 21 2879 2882 20 1 2017 27 2 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment. \n\ndenosumabhypocalcemiagastrectomygastric cancervitamin Dbone turnover\n==== Body\nIntroduction\nBone metastasis leads to skeletal-related events (SREs), including pathologic fracture, the need for radiation or surgical treatment, and spinal cord compression, all of which impair a patient's quality of life. Clinical studies have shown that bone-modifying agents such as zoledronic acid and denosumab can reduce the incidence of SREs (1-3). Although denosumab has been associated with a lower frequency of SREs than zoledronic acid, it has also been associated with a higher frequency of hypocalcemia (4). We herein report a case of severe persistent hypocalcemia in a patient with diffuse bone metastasis of gastric cancer after the administration of a single dose of denosumab. Furthermore, we have identified potential risk factors for hypocalcemia, particularly gastrectomy, which has not been highlighted previously.\n\nCase Report\nA 77-year-old woman was referred to our hospital to undergo treatment for malignant pleural effusions and dyspnea of 2 months' duration. She had undergone total gastrectomy with D2 lymphadenectomy and Roux-en-Y anastomosis for signet ring cell carcinoma of the stomach (pT1bN2M0, Stage IIA; Japanese Classification of Gastric Carcinoma, 14th Edition) (5) 12 years previously.\n\nShe was hospitalized to be evaluated and treated for dyspnea. Upon admission, her height and weight were 134.1 cm and 43.0 kg (body mass index: 23.9 kg/m2), respectively. Her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 3. A laboratory evaluation yielded the following results: elevated levels of alkaline phosphatase (ALP; 5,680 IU/L, normal range: 115-359 IU/L) and carcinoembryonic antigen (CEA; 5.7 ng/mL, normal range: 0.0-5.0 ng/dL); normal levels of calcium (7.9 mg/dL), corrected calcium [serum calcium + (4 - serum albumin); 8.9 mg/dL, normal range: 8.8-10.1 mg/dL], and creatinine (0.51 mg/mL, normal range: 0.40-0.70 mg/dL). The estimated glomerular filtration rate (eGFR) and estimated creatinine clearance (Cockcroft-Gault equation) were 86 mL/min/1.73 m2 and 62.7 mL/min, respectively. Her initial parathyroid hormone (PTH)-intact level was not measured.\n\nComputed tomography revealed bilateral pleural effusion, ascites, and multiple sclerotic bone lesions without any other visceral metastases. No atrophic change of the kidneys was found. Bone scintigraphy revealed diffuse, increased skeletal activity with little renal activity, which met the definition of a super bone scan (Fig. 1) (6). A cytological evaluation of the pleural effusion detected adenocarcinoma, and a cell block specimen showed adenocarcinoma with signet-ring cells that were positive for Ber-EP4 and HNF4α and negative for ER, PAX8, CDX2, and TTF-1, which was compatible with the patient's history of recurrent gastric cancer. She was diagnosed with pleural dissemination of recurrent gastric cancer and although ascites and bone lesions were not pathologically evaluated due to the challenges associated with specimen collection, these were respectively presumed to be malignant ascites and bone metastases of gastric cancer.\n\nFigure 1. Bone scintigraphy. Diffusely increased activity can be seen in the skeleton. Little activity is observed in the kidneys.\n\nThe patient elected to receive supportive care only, given her general condition and preference. To reduce the risk of SREs and maintain her activities of daily living, she received a single dose of denosumab (120 mg, subcutaneously), and the oral supplementation of calcium (610 mg/day), vitamin D (cholecalciferol) (400 IU/day), and magnesium (30 mg/day) was initiated. She was discharged the day after the administration of denosumab.\n\nSix days after the administration of denosumab, she returned to our hospital via ambulance with paralysis and numbness in the hands. Blood tests revealed hypocalcemia (calcium, 4.7 mg/dL; corrected calcium, 6.0 mg/dL), and hypophosphatemia (phosphate, 2.3 mg/dL, normal range: 2.7-4.6 mg/dL), as well as the following additional values: magnesium, 2.8 mg/mL (normal range: 1.5-2.5 mg/dL); creatinine, 0.49 mg/mL; and ALP, 3605 IU/L. She received an infusion of 10 ml of 10% calcium gluconate (with 3.9 mEq calcium) followed by the continuous intravenous administration of calcium (2.5 mEq/h), after which her calcium level normalized. Twelve days after the administration of denosumab, the oral supplementation of calcium, vitamin D, and magnesium was restarted, and intravenous calcium was reduced to a dose equivalent to 18 mEq/day. Within a few hours, she experienced muscle weakness, and the intravenous calcium dosage was increased. Her PTH-intact level was found to be elevated to 375 pg/mL (normal range: 10-65 pg/mL). Fig. 2 shows the corrected calcium levels and the dose of calcium that was administered intravenously each day. Her general condition deteriorated gradually, with increasing pleural effusion and ascites. She required the intravenous administration of calcium until she was transferred to another hospital for palliative care 56 days later. She died 68 days after the administration of denosumab.\n\nFigure 2. Corrected Ca and intravenous Ca were administered each day. Ca: calcium\n\nDiscussion\nDenosumab, a monoclonal antibody that targets the receptor activator of nuclear factor-κB ligand (RANK-L), prevents bone resorption and bone destruction by inhibiting osteoclast activity (3). Three phase III trials demonstrated the superiority of this agent relative to zoledronic acid for the prevention and delay of SREs in patients with bone metastases of cancer (1-3). As mentioned above, hypocalcemia is a common side effect, which affects 5.5-13% of patients (1-3). Notably, a previous report suggested that RANK-L inhibitors are associated with a greater suppression of bone resorption and calcium release in comparison to bisphosphonates (7).\n\nThe factors associated with an increased risk of hypocalcemia include renal insufficiency, high bone turnover, and lack of vitamin D and calcium supplementation (8, 9). In our case, denosumab-induced hypocalcemia persisted for at least 7 weeks and necessitated the intravenous administration of calcium, despite the oral supplementation of calcium, vitamin D, magnesium, and phosphate. We hypothesize that the patient's history of total gastrectomy, increased bone turnover, and insufficient additional PTH secretion in response to decreased calcium were responsible for the duration and severity of hypocalcemia.\n\nThis report suggests that total gastrectomy with Roux-en-Y anastomosis, rather than gastric cancer, contributed to the development of hypocalcemia. Recently, a retrospective study of patients who received denosumab identified gastric cancer as an independent risk factor for hypocalcemia (10). Because gastrectomy did not increase the risk of hypocalcemia in that analysis, the researchers claimed that a gastrointestinal malfunction in patients with gastric cancer might be a mechanism underlying hypocalcemia, irrespective of gastrectomy. However, fewer than 15 patients with gastric cancer were analyzed in that study, which was the number of cases in which denosumab was administered. Furthermore, the report did not consider the type of gastrectomy (total or partial gastrectomy) or reconstruction.\n\nThe mechanisms of calcium and vitamin D absorption suggest that hypocalcemia associated with total gastrectomy and Roux-en-Y anastomosis is more likely caused by malabsorption. For example, the use of Roux-en-Y anastomosis in bariatric surgery was associated with malabsorption of calcium and vitamin D (11). Another study reported suspected osteomalacia in 25% of post-gastrectomy patients and observed a correlation between fat malabsorption and abnormal calcium metabolism (12). Fat malabsorption is a known complication of gastrectomy with Roux-en-Y anastomosis (13) and can lead to impaired vitamin D absorption, as calcium is ionized and solubilized by gastric acid (14). After total gastrectomy, reduced gastric acid secretion would impair calcium ionization; furthermore, in patients with a Roux-en-Y anastomosis, chyme does not pass through the duodenum, where calcium is primarily absorbed (14). Extra caution should be taken when treating patients who have undergone gastrectomy because they may not absorb orally supplemented calcium or vitamin D. To the best of our knowledge, this is the first case report to demonstrate the possibility of an association between total gastrectomy and denosumab-related hypocalcemia.\n\nDiffuse bone metastases, elevated ALP levels, and a poor PS are reported risk factors for hypocalcemia and may have led to denosumab-induced hypocalcemia in our patient. Although we did not measure the bone-specific ALP level, diffuse bone metastases and an elevated ALP level suggest a high bone metabolism. A pooled analysis of three phase III studies of denosumab found that the number of bone metastases, an elevated bone-specific ALP level, and an elevated urinary N-telopeptide level, which are indicators of high bone turnover, are also risk factors for hypocalcemia (8). Furthermore, a poor PS was reported to be a risk factor for hypocalcemia (10). Altogether, this patient was probably at very high risk of developing denosumab-induced hypocalcemia.\n\nDenosumab-induced hypocalcemia may persist in patients without an appropriate hormonal response to a decreased calcium level. In a phase II study that compared different denosumab doses and dosing schedules, a decrease in a urinary bone turnover marker persisted for 12 weeks after a single dose (15). Thus, bone resorption may be inhibited for at least 12 weeks. The persistence of hypocalcemia may depend on the patient's ability to compensate for this decreased calcium level. Previous case reports have described patients with prolonged denosumab-induced hypocalcemia who required intravenous calcium administration for more than 26 days (16-18). One of these reports identified the potential contributions of a gastrointestinal loss of calcium and normocalcemic hyperparathyroidism (18), with an inability to secrete additional PTH in response to a decreased calcium level. Although the baseline vitamin D, phosphate, and PTH levels were not measured in our case, it was hypothesized that the patient did not respond to decreased calcium levels and experienced persistent hypocalcemia requiring intravenous calcium administration for more than 50 days due to a gastrectomy-related loss of calcium and preexisting normocalcemic hyperparathyroidism.\n\nThe present study is associated with some limitations. First, it is possible that the PTH-intact level increased due to chronic renal dysfunction as the baseline PTH-intact level was not measured and the assessment of the patient's kidney function was not thorough (24-hour urine collection was not performed). However, with the available data on the patient's renal function and the rarity (8%) of PTH-intact elevation (≥70 pg/mL) in patients with an eGFR of ≥60 mL/min/1.73 m2 (19), we believe that a marked increase in the PTH-intact level due to chronic renal dysfunction was unlikely. Second, in the present study, we only report one case. The association between gastrectomy and denosumab-induced hypocalcemia needs to be further evaluated in a larger number of patients with and without prior total gastrectomy. Nonetheless, it would be meaningful for clinicians to keep in mind the possibility that gastrectomy may increase the risk of denosumab-induced hypocalcemia and to identify potentially high-risk patients.\n\nTotal gastrectomy with Roux-en-Y anastomosis may be a risk factor for denosumab-induced hypocalcemia. This condition can persist in patients with impaired hormonal responses to decreased calcium levels. It is important to thoroughly evaluate bone and calcium homeostasis, including the nutritional status associated with gastrointestinal manipulation, and the extent of bone metastasis and turnover prior to the initiation of denosumab therapy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nStopeck AT , Lipton A , Body JJ , et al \nDenosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study . J Clin Oncol \n28 : 5132 -5139 , 2010 .21060033 \n2. \nFizazi K , Carducci M , Smith M , et al \nDenosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study . Lancet \n377 : 813 -822 , 2011 .21353695 \n3. \nHenry DH , Costa L , Goldwasser F , et al \nRandomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma . J Clin Oncol \n29 : 1125 -1132 , 2011 .21343556 \n4. \nLipton A , Fizazi K , Stopeck AT , et al \nSuperiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials . Eur J Cancer \n48 : 3082 -3092 , 2012 .22975218 \n5. \nJapanese classification of gastric carcinoma: 3rd English edition . Gastric Cancer \n14 : 101 -112 , 2011 .21573743 \n6. \nManier SM , Van Nostrand D \nSuper bone scan . Semin Nucl Med \n14 : 46 -47 , 1984 .6710165 \n7. \nMorony S , Warmington K , Adamu S , et al \nThe inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy . Endocrinology \n146 : 3235 -3243 , 2005 .15845617 \n8. \nBody JJ , Bone HG , de Boer RH , et al \nHypocalcaemia in patients with metastatic bone disease treated with denosumab . Eur J Cancer \n51 : 1812 -1821 , 2015 .26093811 \n9. \nWatkins KR , Rogers JE , Atkinson B \nTolerability of denosumab in metastatic solid tumor patients with renal insufficiency . Support Care Cancer \n23 : 1657 -1662 , 2015 .25421444 \n10. \nKinoshita Y , Arai M , Ito N , et al \nHigh serum ALP level is associated with increased risk of denosumab-related hypocalcemia in patients with bone metastases from solid tumors . Endocr J \n31 : 479 -484 , 2016 .\n11. \nBland CM , Quidley AM , Love BL , Yeager C , McMichael B , Bookstaver PB \nLong-term pharmacotherapy considerations in the bariatric surgery patient . Am J Health Syst Pharm \n73 : 1230 -1242 , 2016 .27354038 \n12. \nEddy RL \nMetabolic bone disease after gastrectomy . Am J Med \n50 : 442 -449 , 1971 .5572594 \n13. \nStael von , Holstein C , Walther B , Ibrahimbegovic E , Akesson B \nNutritional status after total and partial gastrectomy with Roux-en-Y reconstruction . Bri J Surg \n78 : 1084 -1087 , 1991 .\n14. \nBronner F , Pansu D \nNutritional aspects of calcium absorption . J Nutr \n129 : 9 -12 , 1999 .9915868 \n15. \nLipton A , Steger GG , Figueroa J , et al \nRandomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases . J Clin Oncol \n25 : 4431 -4437 , 2007 .17785705 \n16. \nShafqat H , Alquadan KF , Olszewski AJ \nSevere hypocalcemia after denosumab in a patient with acquired Fanconi syndrome . Osteoporos Int \n25 : 1187 -1190 , 2014 .24158473 \n17. \nTeng J , Abell S , Hicks RJ , et al \nProtracted hypocalcaemia following a single dose of denosumab in humoral hypercalcaemia of malignancy due to PTHrP-secreting neuroendocrine tumour . Clin Endocrinol \n81 : 940 -942 , 2014 .\n18. \nMilat F , Goh S , Gani LU , et al \nProlonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer . Bone \n55 : 305 -308 , 2013 .23685544 \n19. \nMuntner P , Jones TM , Hyre AD , et al \nAssociation of serum intact parathyroid hormone with lower estimated glomerular filtration rate . Clin J Am Soc Nephrol \n4 : 186 -194 , 2009 .19019998\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(21)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "bone turnover; denosumab; gastrectomy; gastric cancer; hypocalcemia; vitamin D", "medline_ta": "Intern Med", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D002118:Calcium; D000069448:Denosumab; D005260:Female; D005743:Gastrectomy; D006801:Humans; D006996:Hypocalcemia; D012307:Risk Factors; D013274:Stomach Neoplasms; D014807:Vitamin D", "nlm_unique_id": "9204241", "other_id": null, "pages": "2879-2882", "pmc": null, "pmid": "28943574", "pubdate": "2017-11-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25421444;26860123;22975218;21343556;24158473;21573743;9915868;19019998;26093811;1933192;15845617;17785705;21060033;6710165;27354038;21353695;5572594;24890549;23685544", "title": "Prolonged Hypocalcemia Following a Single Dose of Denosumab for Diffuse Bone Metastasis of Gastric Cancer after Total Gastrectomy.", "title_normalized": "prolonged hypocalcemia following a single dose of denosumab for diffuse bone metastasis of gastric cancer after total gastrectomy" }

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{ "abstract": "A 77-year-old African American female with rheumatoid arthritis presented with fever and unsteady gait. She was started on broad-spectrum antimicrobials due to CT evidence for sacroiliitis and psoas abscess and underwent partial excision of her sacroiliac bone and drainage of the abscess. One of four blood cultures grew Enterococcus faecalis and the patient was sent home with intravenous ampicillin for 6 weeks. Two days after antimicrobial completion, the patient presented with night sweats and weakness. Chest x-ray revealed new right upper lobe pulmonary infiltrates, and the AFB culture sent during her prior admission returned positive for TB. RIPE therapy with moxifloxacin was initiated. Although she responded well to treatment, she retained functional immobility. We report a case of musculoskeletal TB initially misdiagnosed as enterococcus sacroiliitis, resulting in a delayed initiation of anti-tuberculous therapy. A high index of suspicion and rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis.", "affiliations": "Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.;Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA.", "authors": "Chandradevan|Raguraj|R|;Takeda|Hironobu|H|;Lim|Tanna|T|;Patel|Nidhip|N|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2020.e00858", "fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30166-9\n10.1016/j.idcr.2020.e00858\ne00858\nArticle\nMycobacterium tuberculosis concealed by enterococcal sacroiliitis\nChandradevan Raguraj Takeda Hironobu Lim Tanna Patel Nidhip nidhip.patel@northside.com⁎ Graduate Medical Education-Northside Hospital Gwinnett, Lawrenceville, GA, USA\n⁎ Corresponding author at: Internal Medicine/Graduate Medical Education, Northside Hospital Gwinnett, 1000 Medical Center Blvd, Lawrenceville, GA, 30046, USA. nidhip.patel@northside.com\n01 6 2020 \n2020 \n01 6 2020 \n21 e0085818 5 2020 29 5 2020 29 5 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 77-year-old African American female with rheumatoid arthritis presented with fever and unsteady gait. She was started on broad-spectrum antimicrobials due to CT evidence for sacroiliitis and psoas abscess and underwent partial excision of her sacroiliac bone and drainage of the abscess. One of four blood cultures grew Enterococcus faecalis and the patient was sent home with intravenous ampicillin for 6 weeks. Two days after antimicrobial completion, the patient presented with night sweats and weakness. Chest x-ray revealed new right upper lobe pulmonary infiltrates, and the AFB culture sent during her prior admission returned positive for TB. RIPE therapy with moxifloxacin was initiated. Although she responded well to treatment, she retained functional immobility. We report a case of musculoskeletal TB initially misdiagnosed as enterococcus sacroiliitis, resulting in a delayed initiation of anti-tuberculous therapy. A high index of suspicion and rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis.\n\nKeywords\nMusculoskeletal tuberculosisDiagnostic delaysIliopsoas abscess\n==== Body\nIntroduction\nTuberculosis is a leading cause of death worldwide [1]. Even though considerable progress has been made in reducing incidence in United States, the goal of eliminating the disease from the US remains elusive [2]. Lengthy treatment duration and delay in diagnosis are associated with multidrug-resistant and extensively drug-resistant tuberculosis. Proactive screening for tuberculosis using best available diagnostics, making accurate and early diagnoses of drug-sensitive or drug-resistant tuberculosis, and initiating appropriate treatment are crucial steps to reduce morbidity and further transmission within the community [3]. Approximately 20–30% of reported cases purely involve extrapulmonary sites. Skeletal tuberculosis is reported in 3–5% of cases [4]. The lack of suspicion, long culture period, and scant experience of providers accounts for a delay between the initial symptoms and the definite diagnosis of skeletal tuberculosis [5]. Our case represents the presence of another organism with tuberculosis, creating a diagnostic dilemma of musculoskeletal tuberculosis and explains the usefulness of rapid detection with TB-PCR to avoid the delay in diagnosis.\n\nCase report\nA 77-year-old African American female with hypertension and rheumatoid arthritis on chronic prednisone therapy presented to the hospital with fever, weakness, and unsteady gait. The patient had a history of latent tuberculosis infection reportedly treated over 15 years ago, and abdominal lymphadenopathy with granulomatous histology of unknown etiology three years ago. Laboratory testing showed normal hemoglobin, elevated leukocyte count of 35,000 cells/μL, and normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Her liver and kidney function were normal, and electrolytes were within normal limits. Physical examination revealed high fever and limited left hip mobility due to weakness and pain. Computed tomography of the hip joint revealed progressive destruction of her sacroiliac joint and a 10 × 8 × 7-centimeter (cm) fluid collection in front of her left iliopsoas muscle (Fig. 1, Fig. 2). A presumptive diagnosis of pyogenic sacroiliitis and psoas abscess were made and the patient was placed on broad-spectrum antimicrobials.Fig. 1 Left psoas abscess (red arrows) and destructive sacroiliac joint (green arrow) in an axial computed tomography scan with intravenous contrast (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).\n\nFig. 1Fig. 2 Coronal section in an abdomen and pelvis computed tomography scan with intravenous contrast showing the left psoas abscess.\n\nFig. 2\n\nThe patient underwent saucerization and partial excision of her left ilium and sacrum, surgical placement of antimicrobial beads, and drainage of the psoas abscess. Biopsy from the bone and drainage from the psoas abscess were also sent for further evaluation. The bone biopsy revealed ill-defined granulomas and the gram stain, AFB stain, GMS stain. and bacterial cultures of the psoas drainage were negative. Samples were sent for tuberculosis and fungal cultures. One out of four blood culture bottles grew Enterococcus faecalis sensitive to ampicillin. Given that all other testing was negative, the patient was sent to a nursing home with intravenous ampicillin therapy for a six-week course. Two days after completing treatment, the patient presented to the hospital again with recurrence of symptoms especially with nightly high fevers and weakness. Laboratory findings were only significant for an elevated WBC of 12,000 cells/μL. CT revealed healing sacroiliitis, no obvious new abscess, and post-surgical placement of antimicrobial beads (Fig. 3). Initial consideration was incomplete treatment given the timing of the symptoms after cessation of antimicrobials; however, the previous AFB culture coincidentally was found to be positive in the seventh week, and TB was confirmed by PCR from the culture positive samples. During the initial encounter,the patient underwent a CXR as a routine work up which didn’t show any infiltrates; however during further work up after the AFB culture, a CXR was repeated and revealed new right upper lobe infiltrates suggestive of pulmonary tuberculosis (Fig. 4).Fig. 3 Axial computed tomography film with intravenous contrast during the second presentation showing post surgical drainage and antimicrobial beads placed (blue) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).\n\nFig. 3Fig. 4 Postero-anterior chest X ray film showing right upper lobe infiltrates.\n\nFig. 4\n\nThe patient did not present with respiratory symptoms; however, she was placed in respiratory isolation and sputum was tested for AFB. She was started on rifampin, isoniazid, pyrazinamide and ethambutol (RIPE) therapy, with the addition of moxifloxacin to also cover for multi-drug resistant tuberculosis (MDR-TB). The patient’s fever subsided after one week of treatment, and after two weeks of treatment she markedly improved and had negative AFB smear and PCR on induced sputum. She was released from isolation precautions and discharged with follow up with the public health department. At the time of discharge, the patient exhibited functional decline and deconditioning due to prolonged hospital stay as well as chronic debilitating illness. She was assessed by physical therapy using Barthel Index score which is a measurement of activities of daily living and revealed a value of 45 points and partially independent. She was placed in a sub-acute rehabilitation facility after inpatient hospital discharge.\n\nDiscussion\nIn skeletal tuberculosis, the onset of symptoms is generally insidious, and not accompanied by alarming general manifestations such as fever, night sweats or extreme weakness [6]. In tuberculous sacroiliitis, there is usually considerable delay between presentation and diagnosis, mainly due to its insidious onset, nonspecific clinical picture, and low clinical index of suspicion. Studies have reported a mean time from symptom onset to diagnosis of 8 months in a series of sacroiliac joint tuberculosis [7]. The diagnosis in our patient was also delayed for 6 weeks despite the recognition and drainage of psoas abscess and pathological analysis of debrided tissue. This is probably due to an atypical clinical picture of tuberculosis and presence of concomitant bacteremia.\n\nA definitive diagnosis of skeletal tuberculosis can be made based on findings of the culture and pathological tests of infected tissues, but these cultures are only positive at a rate of 50–75 %, making bacteriologic confirmation of the disease very difficult [8]. RT-PCR assays have a high degree of sensitivity, making them a suitable test to rule out TB infection. RT-PCR assays demonstrate rapidity of detection of TB, which is an important factor in initiating early and appropriate anti-tuberculosis therapy. PCR can play an important role in rapid and accurate diagnosis of extrapulmonary tuberculosis. The percentage of specimen positive by smear, culture, and PCR was 20.3%, 23.6 %, and 45.3%, respectively, for the diagnosis of extrapulmonary tuberculosis in one study [9].\n\nThe rapid results of PCR aid in early institution of anti-tuberculosis treatment and thus controlling the spread of disease. Further, in this case, it was difficult to detect the tubercle bacilli until the culture became positive. Moreover, we were hesitant to start anti-tuberculosis medications in the setting of enterococcal bacteremia. During the six weeks course of treatment patient did not have a fever and pain was markedly reduced to ease her participation in physical therapy. We believe this is due to radical debridement of the sacroiliitis and treatment response to co-existing bacterial sacroiliitis. Presence of tuberculosis with bacterial infections in immunocompetent patients has been reported in the past, and we believe our patient acquired concomitant infectious processes with enterococcal bacteremia and mycobacteria infection [10]. Negative bacterial culture and stains from the abscess, enterococcal bacteremia and treatment response with ampicillin appropriately dictated immediate antimicrobial therapy; however, it caused anchoring to a diagnosis without considering the patient’s high risk for concomitant TB.\n\nIn the case of an elderly woman with known TB exposure, chronic immunosuppression secondary to prednisone therapy, pyogenic abscess to an area typical for TB, granulomatous pathology of bone biopsy, and previous biopsy with granulomatous nodules in the abdomen should have led to earlier PCR testing or empiric TB treatment on initial presentation. TB is a slow growing acid-fast bacillus and waiting for culture results can cause a delay in diagnosis and further morbidity, as in our case.\n\nConclusion\nTuberculous sacroiliitis is a disabling condition and can often be overlooked. Keeping a high index of suspicion for TB in high-risk individuals and considering more rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis and increased morbidity from delay in treatment.\n\nAuthor contributions\nRaguraj Chandradevan helped conceptualize the paper, contributed to data acquisition, wrote the manuscript, and reviewed and approved the final manuscript.\n\nHironobu Takeda and Tanna Lim helped conceptualize the paper, contributed to data acquisition, and reviewed and approved the final manuscript.\n\nNidhip Patel is the investigator of this project and responsible for the overall conduct, results and conclusions of the paper. He conceptualized the paper, contributed to the manuscript, and reviewed and approved the final manuscript.\n\nFunding\nThere was no funding or sponsorship for this report.\n\nEthical approval\nThis study was approved by Graduate Medical Education at Northside Hospital Gwinnett.\n\nConsent\nWe obtained the patient’s consent to publish the case report. The patient accepts the publication of this case report.\n\nDeclaration of Competing Interest\nThe authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Glaziou P. Sismanidis C. Floyd K. Raviglione M. Global epidemiology of tuberculosis Cold Spring Harb Perspect Med 5 2 2014 a017798 \n2 Langer A.J. Navin T.R. Winston C.A. LoBue P. Epidemiology of tuberculosis in the United States Clin Chest Med 40 4 2019 693 702 31731978 \n3 Gilpin C. Korobitsyn A. Weyer K. Current tools available for the diagnosis of drug-resistant tuberculosis Ther Adv Infect Dis 3 6 2016 145 151 28386407 \n4 Pigrau-Serrallach C. Rodriguez-Pardo D. Bone and joint tuberculosis Eur Spine J 22 Suppl 4 2013 556 566 \n5 Broderick C. Hopkins S. Mack D.J.F. Aston W. Pollock R. Skinner J.A. Delays in the diagnosis and treatment of bone and joint tuberculosis in the United Kingdom Bone Joint J 100–B 1 2018 119 124 \n6 Garg R.K. Somvanshi D.S. Spinal tuberculosis: a review J Spinal Cord Med 34 5 2011 440 454 22118251 \n7 Zhu G. Jiang L.Y. Yi Z. Ping L. Duan C.Y. Yong C. Sacroiliac joint tuberculosis: surgical management by posterior open-window focal debridement and joint fusion BMC Musculoskelet Disord 18 1 2017 504 29187182 \n8 Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence Clin Microbiol Rev 16 3 2003 463 496 12857778 \n9 Raveendran R. Wattal C. Utility of multiplex real-time PCR in the diagnosis of extrapulmonary tuberculosis Braz J Infect Dis 20 3 2016 235 241 27020707 \n10 Attia E.F. Pho Y. Nhem S. Sok C. By B. Phann D. Tuberculosis and other bacterial co-infection in Cambodia: a single center retrospective cross-sectional study BMC Pulm Med 19 1 2019 60 30866909\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "21()", "journal": "IDCases", "keywords": "Diagnostic delays; Iliopsoas abscess; Musculoskeletal tuberculosis", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "e00858", "pmc": null, "pmid": "32566481", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "31731978;29187182;25359550;22711012;30866909;27020707;29305460;12857778;28386407;22118251", "title": "Mycobacterium tuberculosis concealed by enterococcal sacroiliitis.", "title_normalized": "mycobacterium tuberculosis concealed by enterococcal sacroiliitis" }

[ { "companynumb": "US-TEVA-2020-US-1802811", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated tuberculosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Loss of personal independence in daily activities", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sacroiliitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CHANDRADEVAN R, TAKEDA H, LIM T, PATEL N. MYCOBACTERIUM TUBERCULOSIS CONCEALED BY ENTEROCOCCAL SACROILIITIS. IDCASES 2020?:.", "literaturereference_normalized": "mycobacterium tuberculosis concealed by enterococcal sacroiliitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20200721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18050793, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586.\n\n\n\nA randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models.\n\n\n\nThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low.\n\n\n\nNo clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges.\n\n\n\nNCT01526057.", "affiliations": "Pfizer Inc., San Diego, California, USA.;Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., New York, New York, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., Cambridge, Massachusetts, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., San Diego, California, USA.;Pfizer Inc., Cambridge, Massachusetts, USA.;Pfizer Inc., San Diego, California, USA.", "authors": "Williams|Jason H|JH|;Hutmacher|Matthew M|MM|;Zierhut|Matthew L|ML|;Becker|Jean-Claude|JC|;Gumbiner|Barry|B|;Spencer-Green|George|G|;Melia|Lisa A|LA|;Liao|Kai-Hsin|KH|;Suster|Matthew|M|;Yin|Donghua|D|;Li|Ruifeng|R|;Meng|Xu|X|", "chemical_list": "D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; D000069283:Rituximab", "country": "England", "delete": false, "doi": "10.1111/bcp.13094", "fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin Pharmacol10.1111/(ISSN)1365-2125BCPBritish Journal of Clinical Pharmacology0306-52511365-2125John Wiley and Sons Inc. Hoboken 2753037910.1111/bcp.13094BCP13094MP-00054-16.R1Pharmacokinetic Dynamic RelationshipsPharmacokinetic Dynamic RelationshipsComparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab Comparative assessment of clinical response for PF‐05280586 and rituximabJ. H. Williams et al.Williams Jason H. \n1\nHutmacher Matthew M. \n2\nZierhut Matthew L. \n1\nBecker Jean‐Claude \n3\nGumbiner Barry \n1\nSpencer‐Green George \n4\nMelia Lisa A. \n1\nLiao Kai‐Hsin \n1\nSuster Matthew \n1\nYin Donghua donghua.yin@pfizer.com \n1\nLi Ruifeng \n4\nMeng Xu \n1\n1 Pfizer Inc.San DiegoCaliforniaUSA2 Ann Arbor Pharmacometrics GroupAnn ArborMichiganUSA3 Pfizer Inc.New YorkNew YorkUSA4 Pfizer Inc.CambridgeMassachusettsUSA* Correspondence Donghua Yin, Pfizer Inc, 10777 Science Center Drive, CB1, San Diego, California 92121, USA. Tel.: +1 858 526 4942; E‐mail: donghua.yin@pfizer.com22 9 2016 12 2016 22 9 2016 82 6 10.1111/bcp.v82.61568 1579 19 1 2016 08 7 2016 08 8 2016 © 2016 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Aims\nTo evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586.\n\nMethods\nA randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models.\n\nResults\nThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low.\n\nConclusions\nNo clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: NCT01526057.\n\nBiosimilarpharmacodynamicspharmacokinetics source-schema-version-number2.0component-idbcp13094cover-dateDecember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:24.11.2016\n\n\nWilliams , J. H. \n, \nHutmacher , M. M. \n, \nZierhut , M. L. \n, \nBecker , J. ‐C. \n, \nGumbiner , B. \n, \nSpencer‐Green , G. \n, \nMelia , L. A. \n, \nLiao , K. ‐H. \n, \nSuster , M. \n, \nYin , D. \n, \nLi , R. \n, and \nMeng , X. \n (2016 ) Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab . Br J Clin Pharmacol , 82 : 1568 –1579 . doi: 10.1111/bcp.13094.27530379\n==== Body\nWhat is Already Known about this Subject\n\nPharmacodynamics and clinical response data collected during early clinical pharmacology studies can add to the totality of the evidence, reduce residual uncertainty, in support of the overall demonstration of biosimilarity, as described in regulatory guidance. However, no report is available to share the knowledge on and experience with this topic.\n\n\n\n\nWhat this Study Adds\n\nThis analysis introduces an objective approach to define ‘meaningful effect’ and quantifies a reference range in which to perform comparative assessments.\n\nModel‐based approaches may help reduce the number of studies necessary to demonstrate biosimilarity to bring affordable versions of biologics to patients who otherwise have no or limited access.\n\n\n\n\nTables of Links\n\n\nTARGETS\n\t\t\n\nOther protein targets\n2\n\t\t\n\nCD20\n\t\nTNF‐alpha\n\t\n\nLIGANDS\n\t\t\n\nRituximab\n\t\t\nThese Tables lists key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.\n\n\n\n\nIntroduction\nTherapies based on biologics are increasingly important in treating many diseases due to their success in addressing previously unmet medical needs. In particular, biologics have greatly improved the management of rheumatoid arthritis (RA), demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion and preventing loss of function 3. However, access to biologic medicines can be limited, particularly in resource‐constrained countries 4. Biosimilars, biologic products that are highly similar to a reference product in terms of quality, biological activity, safety and efficacy, are expected to be an essential component in reducing health care costs and enhancing patient access to these important, often lifesaving medications 4. In the USA, the Biologics Price Competition and Innovation Act of 2009 established an abbreviated pathway for US Food and Drug Administration (FDA) licensure of products that are biosimilar to a licensed reference product 5. Similar regulatory pathways for biosimilar applications have been established elsewhere 6, 7. A key component of the abbreviated pathway is extrapolation of clinical data to one or more additional indications 6, 8.\n\nThe role of clinical pharmacology studies in demonstration of biosimilarity is emphasised in the FDA's guidance for industry 9. These studies provide data that describe the degree of similarity in drug exposure, also referred to as pharmacokinetic (PK) similarity, between the proposed biosimilar and reference product(s). In addition, clinical pharmacology studies often include pharmacodynamic (PD) end points and pharmacometric analyses to assess whether clinically meaningful differences exist between the proposed biosimilar and reference product(s). Clinical pharmacology data can add to the totality of the evidence and reduce residual uncertainty, thus guiding the need for, and design of, subsequent clinical testing. Furthermore, clinical pharmacology data can provide scientific justification supporting extrapolation of clinical data to one or more additional indications.\n\nRituximab is a chimeric anti‐CD20 monoclonal antibody that selectively targets and depletes B cells and has demonstrated significant clinical benefit in patients with RA and non‐Hodgkin's lymphoma 10, 11. PF‐05280586 has the same primary amino acid sequence as rituximab, with similar physicochemical and in vitro functional properties, and is under development as a potential biosimilar to rituximab 12, 13. The PK similarity of PF‐05280586 to rituximab sourced from the European Union (rituximab‐EU) and US (rituximab‐US), as well as PK similarity of rituximab‐EU to rituximab‐US, was demonstrated in a multicentre, multinational, randomised double‐blind, controlled trial in patients with active RA on a background of methotrexate who had an inadequate response to one or more tumour necrosis factor antagonist therapies 12. Use of reference products sourced from different regions (i.e. EU and US) is part of standard PK similarity study design for not only meeting the reference‐specific PK similarity requirement but also for providing scientific justification for use of a single reference product in subsequent trials 8.\n\nThis trial was designed to demonstrate PK similarity, yet clinical response end points were also collected during the 24‐week study period. The study was therefore not powered for standard statistical evaluation of efficacy. Using a population PK/PD (PopPK/PD) modelling approach that was planned prospectively, analysis of clinical end points was conducted to assess any potential clinically meaningful difference between the proposed biosimilar and a reference product. The approach took advantage of the multiple repeated measurements for each clinical end point and variability observed between the two reference products using the assumption that differences in clinical responses between the two reference products would not be clinically meaningful if PK similarity was established. The key aspect of this approach was to utilise data from the two reference arms for constructing a reference range of ‘no clinically meaningful difference’ for comparative assessments of PF‐05280586 to the reference products. We present this PopPK/PD modelling analysis as a case study for utilizing clinical response data from a clinical pharmacology study to add to the overall demonstration of biosimilarity.\n\nMethods\nThis study is registered at ClinicalTrials.gov (NCT01526057) and was conducted in compliance with the Declaration of Helsinki and with all International Conference on Harmonisation Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol, amendments and informed consent documentation were reviewed and approved by Institutional Review Boards and/or Independent Ethics Committees at each participating centre. A signed and dated informed consent was required from each patient before any screening procedures were conducted.\n\nStudy design\nThe study was a randomised, double‐blind, controlled trial in patients with active RA on a background of methotrexate who had inadequate responses to one or more tumour necrosis factor antagonist therapies 12. The primary objective was to demonstrate PK similarity of PF‐05280586, rituximab‐EU and rituximab‐US. The secondary objectives included those described herein, which were to use PopPK/PD modelling approaches to integrate PK and PD data for the purpose of detecting potential differences in PK/PD profiles. Other secondary objectives included evaluation of overall safety, tolerability and immunogenicity. The results of this study, except for those from the PopPK/PD modelling, have been presented elsewhere 12. Full details of the study design have been described 12. Briefly, eligible participants were adults (aged ≥18 years) with confirmed diagnosis of RA based on 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria 14. Patients were required to: meet class I, II or III of the ACR 1991 revised criteria for Global Functional Status in Rheumatoid Arthritis 15; have RA seropositivity, as documented by a screening assessment for rheumatoid factor; and/or anticyclic citrullinated peptide antibodies; active disease, as defined by the following: at least six tender/painful joints (of 68 assessed) and six or more swollen joints (of 66 assessed) at screening and baseline, high‐sensitivity C‐reactive protein (CRP) greater than the upper limit of normal, or Patient's Global Assessment of arthritis score ≥50 at screening, and Disease Activity Score in 28 joints (DAS28)–CRP >3.2 at screening; be on a stable dose of oral or parenteral methotrexate 10–25 mg per week (or as low as 7.5 mg per week, in the case of prior poor tolerance) for at least 3 months and receiving the stable dose for at least 4 weeks prior to first dose of study drug; and have inadequate response, in the opinion of the investigator, to one or more approved TNF‐antagonist therapies, defined as failure to achieve adequate clinical response during prior TNF‐antagonist therapy, relapse following clinical response to TNF‐antagonist therapy or an adverse event resulting in discontinuation of TNF antagonist. A sample size calculation based on standard bioequivalence determined that up to 210 subjects were to be enrolled to ensure at least 195 subjects (65 subjects in each treatment arm) completed the study procedures per protocol. The PopPK/PD analysis population was defined as all randomised subjects who receive full doses of the assigned study treatment and had at least one protocol‐specified measurement for drug concentration and the PD response of interest collected after receiving study treatment, as well as the respective baseline values. Patients received 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US by intravenous infusion on days 1 and 15. All subjects were to receive premedication with 100 mg intravenous methylprednisolone (or its equivalent) prior to each infusion.\n\nClinical response\nEfficacy following rituximab therapy in patients with RA included improvements in measures of clinical response such as DAS28 and categorical American College of Rheumatology (ACR) response 16, 17, 18. DAS28 is a function of four components: tender joint counts 28 (TJ28) and swollen joint counts 28 (SJ28), CRP and patient's global assessment of arthritis (PGA). The ACR responder criteria are a function of a core set of seven components: TJ68, SJ66, CRP, PGA, Health Assessment Questionnaire Disability Index, patient's assessment of arthritis pain, and physician's global assessment of arthritis. A patient was considered a responder on the ACR20 assessment if >20% improvement in tender and swollen joint counts was observed with >20% improvement in three of the five other component variables; ACR50 and ACR70 were defined similarly, with 50% and 70% thresholds, respectively. Components of DAS28 and ACR responder status end points were collected at predose (baseline) and at 2, 4, 8, 12, 16, 20 and 24 weeks after start of treatment.\n\nAn enzyme‐linked immunosorbent assay for determining concentrations of rituximab and PF‐05280586 in human serum samples was developed and validated by QPS, LLC (Newark, DE, USA; see Supplemental Methods). Actual time of collection for all PK and clinical response measurements was used for the analysis.\n\nModel development and implementation\nLongitudinal nonlinear mixed‐effects models were fit to the PK, DAS28 and ACR response data. The models were implemented in NONMEM (Icon Development Solutions, Ellicott City, MD, USA), version 7.1.2 or higher, using first‐order conditional estimation for continuous end points and Laplace estimation for categorical end points. The models were similar to those described for characterization of the time‐course of both continuous 19 and categorical 20, 21, 22, 23 measures of clinical response in patients with RA. As previously described, these models provide a semi‐mechanistic framework to describe the effect functions for both placebo and drug, each of which can include parameters related to the effect onset and maximum. This is more intuitive for continuous end points. For categorical end points, an underlying unobservable ‘latent variable’ (LV) is mapped into binary or ordered categorical response through the probability mass between thresholds. In this way, the threshold parameter is a numerical value on the unobservable continuous scale, which determines positivity on the binary scale. The LV is often assumed to be a function of an indirect response mechanism (e.g. reduction of inflammation) and any acting placebo effects (e.g. a patient's perception of their disease) which may be aggregated into a single clinical response end point (e.g. ACR response rate). Constructing the LV as a function of the indirect response thus yields a pharmacologically interpretable type of model and therefore may be useful for assessing similarity of response between two drug products. In addition, for a more efficient use of ACR response data, simultaneous modelling of ACR20, ACR50 and ACR70 end points were implemented, assuming that ACRm, where m = 20, 50 or 70, was achieved when an m% improvement form baseline was observed 19.\n\nCovariate effects were modelled focusing on components of baseline disease activity appropriate for each clinical response end point, which are centred on their median observed values, and product specific parameters applied to three key model components and were estimated simultaneously. Detailed mathematical descriptions of structures for DAS28 change from baseline (DAS28cfb) and ACR responder models, and procedures for their suitability evaluations and applications for comparative assessments are provided in Supplemental Methods.\n\nReference range for comparative assessments\nThe rationale for using the reference range to define ‘clinically meaningful effect’ relied on the assumption that differences in clinical responses between the two reference products would not be clinically meaningful if PK similarity was established. This assumption is based on the following: two rituximab reference products, while sourced from different regions, share the same prescribing practice for the indications approved in the regions, consistent with the biosimilarity definition based on the principle of no clinically meaningful differences between two biologic products under consideration; and confirmation that equivalent exposures were achieved in the two reference products ensuring that any difference in clinical response between the two are not due to differing exposure.\n\nThe 90% confidence interval (CI) of the model‐predicted difference between area under effect curve (AUEC) means of rituximab‐EU and rituximab‐US treatments defined the reference range for a given clinical response end point. The model predictions of AUEC differences between means for PF‐05280586 and rituximab‐US and between PF‐05280586 and rituximab‐EU were compared with the reference range. Predictions within the reference range implied that no meaningful difference was observed between PF‐05280586 and the reference.\n\nComparative assessments\nMonte Carlo techniques (1000 simulation replicates of 10 000 individuals per arm) were used to derive the 90% CIs used for the comparative assessments. A smoothed parametric bootstrap procedure was used to generate the Monte Carlo replicates in which vectors of parameters were drawn for each simulated replicate from a multivariate normal distribution, with mean vector equal to the population model estimates and uncertainty incorporated via the estimated covariance matrix of these population estimates. Additionally, a covariate vector for each individual within the replicate was sampled from the empirical distribution of the study using a bootstrap technique with replacement of patients during resampling. The bootstrap technique was not stratified by treatment to ensure covariate distributions were balanced on average across the groups over the simulated replicates. From these simulated data, population AUEC means were computed across the individual and the covariate distribution per replicate and per arm to derive the prediction for the replicate. The predictions were not dependent upon the individual covariate effects, because these were integrated from the population mean prediction. Thus, differences between treatments were based on fixed effects of treatment differences and their uncertainties. The 90% CI was calculated using the 5th and 95th percentile from the distribution of the AUEC differences between the test and reference products.\n\nCase–control analysis\nA posthoc case–control analysis was performed as an orthogonal approach to verifying the impact of the imbalance in baseline patient disease characteristics among groups on the comparative assessments. Multivariate and propensity score matching was implemented using the Matching package in R Software (R Foundation for Statistical Computing, Vienna, Austria) 24. Variables selected for inclusion in the propensity score model were based on those that showed an imbalance in the original dataset while also considering observed correlations between different variables. Matching was performed without replacement of subjects using a calliper of one‐quarter the standard deviation of the propensity score. For a given propensity score model, matching was performed first to balance the two reference groups (rituximab‐EU vs. rituximab‐US) using 1:1 matching. The two matched reference groups were then compared for how well balance was achieved. If adequate, matching was then performed using the same propensity score model to balance the reference group (rituximab‐EU/US) to the test group (PF‐05280586) using 2:1 matching. The matched groups were then compared for how well balance was achieved. This process was repeated for various models, which included either a single or multiple variables. Performance was assessed at each step graphically and statistically. Graphical comparison of clinical response measures (DAS28cfb and ACR20 responder rate) between the three balanced treatment groups was performed to show the effects of matching.\n\nResults\nBaseline characteristics\nA total of 214 patients were included in the PopPK/PD modelling analysis population (Table 1). Demographics were similar across groups; however, some imbalances with respect to baseline disease characteristics and duration of RA were noted. Specifically, patients in the rituximab‐US arm had the highest baseline DAS28 with a CRP component, as well as the highest mean values of the individual components that make up DAS28 and ACR assessments. The most noticeable differences were in CRP; PGA and physician's global assessment of arthritis based on visual analogue scale measurements; SJ28 and SJ66; and TJ28 and TJ68. Duration of RA was also shortest in the rituximab‐US group. Taken together, these data indicate that patients randomised to the rituximab‐US group entered the study with more severe yet shorter duration of disease than patients in the rituximab‐EU or PF‐05280586 groups.\n\nTable 1 Patient demographics and baseline disease characteristics for the PK/PD modelling analysis population\n\n\t\nPF‐05280586\n(n = 71)\n\t\nRituximab‐EU\n(n = 72)\n\t\nRituximab‐US\n(n = 71)\n\t\n\nDemographics\n\t\n\nMean age ± SD, years\n\t54.8 ± 11.7\t55.7 ± 10.2\t53.8 ± 11.8\t\n\nMale, n (%)\n\t13 (18.3)\t16 (22.2)\t19 (26.8)\t\n\nMean body weight ± SD, kg\n\t86.2 ± 22.0\t82.6 ± 19.8\t80.4 ± 21.6\t\n\nMean body surface area ± SD,\nm\n2\n\t1.9 ± 0.2\t1.9 ± 0.2\t1.9 ± 0.3\t\n\nMean disease duration since first diagnosis ± SD, years\n\t12.7 ± 8.4\t11.8 ± 8.3\t10.6 ± 8.1\t\n\nDisease characteristics, mean ± SD\n\t\n\nDAS28‐CRP\n\t5.64 ± 0.85\t5.80 ± 0.96\t6.2 ± 0.89\t\n\nHAQ‐DI\n\t1.67 ± 0.56\t1.61 ± 0.53\t1.74 ± 0.62\t\n\nSwollen joint count 28\n\t11.4 ± 5.0\t13.0 ± 6.6\t14.0 ± 6.0\t\n\nTender joint count 28\n\t14.3 ± 6.5\t15.1 ± 6.8\t18.0 ± 6.5\t\n\nSwollen joint count 66\n\t15.4 ± 8.8\t17.9 ± 10.6\t18.9 ± 8.4\t\n\nTender joint count 68\n\t22.7 ± 12.6\t23.7 ± 13.2\t29.7 ± 15.0\t\n\nCRP, mg l\n–1\n\t12.4 ± 14.9\t14.7 ± 17.6\t18.2 ± 25.1\t\n\nPhGA\n\t64.6 ± 15.3\t66.1 ± 15.5\t70.1 ± 15.6\t\n\nPatient's assessment of arthritis pain\n\t65.6 ± 17.8\t66.1 ± 21.0\t72.1 ± 18.5\t\n\nPGA\n\t67.4 ± 16.8\t67.7 ± 20.9\t74.8 ± 16.0\t\nCRP, C‐reactive protein; DAS28‐CRP, Disease Activity Score in 28 joints based on C‐reactive protein; HAQ‐DI, Health Assessment Questionnaire Disability Index; PD, pharmacodynamics; PGA, patient's global assessment of arthritis; PhGA, physician's global assessment of arthritis; PK, pharmacokinetics; SD, standard deviation.\n\nPopulation PK/PD models\nThe DAS28 dataset included 214 baseline and 1382 postbaseline observations. Model development occurred in stages proceeding from modelling DAS28 in normal scale, DAS28cfb scale, inclusion of exposure effects and lastly, inclusion of covariate effects (see Supplemental Results for additional information). Additional details, including the incorporation of between and within‐subject variability, are included in Supplemental Methods.\n\nThe final DAS28cfb model incorporated parameters related to onset (kp\ni) and maximum magnitude (PMAX\ni) of treatment effects to characterise the exponential decline in disease activity following a single course of treatment. A maximum drug effect model dependent on product concentration (Cij) included parameters representing maximum effect (Emaxi) and the concentration at which half the maximal effect is predicted (exp(θEC50)). Subject covariates and drug exposure were predictive of clinical response (Supplemental Table S1). The final DAS28cfb model predictions tracked the central tendency and distribution of DAS28cfb observations (Figure 1). In addition, inspection of plots produced for model validation indicated that the DAS28cfb model was appropriate for comparative assessment of clinical response (data not shown).\n\nFigure 1 Observed and predicted DAS28 change from baseline vs. time, by treatment. The light grey dashed lines and symbols represent individual patient response profiles, and solid lines represent the population predicted mean (PREDavg; black), observed median (red), geometric mean (orange), and individual predicted mean (iPREDavg; blue). The number of patients contributing to each time point is listed along the bottom of the x axis. DAS28, Disease Activity Score in 28 joints\n\nConcentration effects were included in the DAS28cfb model using individual predicted concentrations from the final PopPK model. A total of 2673 observations were included in the PopPK dataset and the percentage of observations below the LLOQ was low (1.5%). Other than those observations excluded that were <LLOQ, two other PK observations were excluded due to a missing sample time or missing data value. The final two‐compartment PopPK model included covariates baseline body surface area and sex on clearance and central volume, similar to previously described in patients with RA 25. The model adequately characterised the time course of drug exposure for all three products as assessed by a visual predictive check (Supplemental Figure S1) and individual prediction plots (not shown).\n\nThe ACR response dataset included 1402 observations. The effect of product treatment on probability of response over time is represented by a function consisting of parameters related to maximum effect (PMAX\ni) and onset of effect (kp\ni), similar to the DAS28cfb model. Unlike the DAS28cfb model, rituximab exposure effects could not be supported in the ACR model.\n\nCovariate effects were predictive of ACR response and lead to some interesting findings. For example, patients with higher numbers of tender joints had a lower probability of being a responder, whereas those with a higher number of swollen joints had a higher probability of response. The population mean predictions tracked the observed data for ACR20, ACR50 and ACR70 in general (Figure 2). In certain cases, the individual predictions captured the trend of the data better than population predicted (e.g. ACR20 for rituximab‐US). This may be in part due to the drop‐out characteristics since the average individual predicted (Figure 2) was only computed over the subjects who remained in the study, and therefore this method or prediction would have the same dropout characteristics as the observed data. This finding, along with inspection of plots produced for model validation (data not shown), indicated the ACR responder rate model was considered accurate for comparative assessment of clinical response.\n\nFigure 2 Observed and predicted ACR20, ACR50 and ACR70 responder rates vs. time, by treatment. Red symbols and error bars represent the observed proportion and ±2 standard errors (SE), respectively, at each time point achieving the defined ACR response criteria. Solid black lines represent the population‐predicted proportion (Pop Mean) and blue lines are mean individual predicted proportion (iPREDavg). The number of patients contributing to each time point is listed along the bottom of the x axis. ACR20/50/70, American College of Rheumatology improvement in rheumatoid arthritis of 20%/50%/70%\n\nComparative reference range\nThe comparative reference range was established from the nonlinear mixed‐effects PopPK/PD model. This range was defined as the 90% CI of the standardised difference between covariate adjusted mean predictions of an integrated clinical response (AUEC) of the two reference arms in this trial. The comparative reference range was −0.05 to 0.57 for DAS28cfb and −0.16 to 0.023 for ACR20 which were approximately similar and somewhat larger, respectively, than the range of clinical responses observed in historic trials 16, 26, 27, 28. The asymmetry (i.e. reference range not centred on zero) was a result of the use of fixed effects in the models to describe clinical response profiles for the two reference products, rather than pooling the two reference arms. The resulting reference range was considered adequate for comparative assessments based on the objective of the analysis. As an alternative approach, which emphasised the absolute differences between the covariate corrected means of the AUEC, an absolute comparative reference range (or boundary) was also established as the 90th percentile of the absolute difference between the covariate corrected means of the AUEC of the two reference arms. This boundary was 0.50 for DAS28cfb and 0.14, 0.13 and 0.099 for ACR20, ACR50 and ACR70, respectively.\n\nComparative assessments\nComparative assessment for the standardised DAS28cfb AUEC mean difference and absolute mean difference between PF‐05280586 and rituximab‐EU (0.076 and 0.083, respectively) and between PF‐05280586 and rituximab‐US (0.32 and 0.33, respectively) showed that the differences were within the comparative reference range and absolute comparative reference range (Figure 3). Similarly, the ACR20 AUEC differences between PF‐05280586 and rituximab‐ EU (−0.016 and 0.012, respectively) and between PF‐05280586 and rituximab‐US (−0.084 and 0.077, respectively; Figure 4) were within the reference range and absolute reference range. This was also confirmed for ACR50 and ACR70 using the absolute mean differences and their reference ranges, respectively (Supplemental Figure S2).\n\nFigure 3 Comparative assessment between PF‐05280586 and two rituximab comparators for DAS28cfb normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for DAS28cfb. AUEC, area under the effect curve; DAS28cfb, Disease Activity Score in 28 joints change from baseline\n\nFigure 4 Comparative assessment between PF‐05280586 and two rituximab comparators for ACR20 responder rates normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (single vertical dashed red line) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for ACR20. ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; AUEC, area under the effect curve\n\nCase–control analysis\nPrior to matching, several subcomponents of DAS28 and ACR response rate were statistically different between reference groups as well as between the pooled reference group (rituximab‐EU/US) and PF‐05280586 group (Supplemental Table S2). A propensity score model, which included two subcomponents, SJ66 and patient's assessment of pain, was sufficient to balance all disease characteristics (including DAS28; Supplemental Table S2). The resulting subset was ~70% of the original dataset. The resulting mean DAS28cfb and ACR20 profiles in this subset of patients showed lack of an effect due to imbalance in baseline patient disease characteristics among all treatment groups compared with those in the original dataset (Figure 5).\n\nFigure 5 Clinical response profiles for three treatment groups before (left panels) and after (right panels) matching, based on swollen joint counts and patient's assessment of pain. Points represent mean (DAS28cfb, top) or proportion (ACR20, bottom). ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; DAS28cfb, Disease Activity Score in 28 joints change from baseline\n\nDiscussion\nWe describe a PopPK/PD approach for comparative assessments of clinical responses between PF‐05280586, a proposed biosimilar to rituximab, and two rituximab products (references) in patients with RA. This approach was designed to take advantage of multiple repeated measurements for each clinical end point and variability observed between the two reference products used in the PK study. A procedure for determining the criteria as to whether a meaningful difference between PF‐05280586 and reference products was observed in the study was prospectively defined, providing a framework for the comparative assessments. Based on these criteria, any mean difference within the reference range would not be considered meaningful. Establishing the reference range relied on the assumption that both reference products had equivalent potency and that, given PK similarity was established, any difference in clinical responses observed between the two references in a single trial are due to study design attributes (not product‐related), such as between‐subject variability or imperfect randomization in baseline disease characteristics among treatment groups. Thus, emphasis is placed on the distribution of differences between references that may be expected between two similar products in a PK trial setting with ~70 subjects per arm. In comparison to historical data extracted from several randomised clinical trials, reference ranges established in this trial are similar in size to those observed across trials for DAS28 but somewhat larger than those for ACR20 16, 26, 27, 28.\n\nThe traditional approach – using ACR clinical response rate at the end of a specified period as the primary end point in randomised clinical trials to distinguish active treatment from placebo – may not be optimal for the biosimilarity assessment between two active treatments especially when the clinical dose is located on the plateau of the dose response curve 22, 29. This limitation was a motivating factor for utilizing the repeated clinical response measurements for the model‐based comparative assessments, along with assessment of another clinical response endpoint (i.e. DAS28), in an attempt to improve detection of a potential difference and add to the totality of evidence for demonstration of biosimilarity. Integrating all PK/PD (clinical response) measurements over time using the model‐based approach allowed examination of onset of effect and magnitude of response along with precise estimation of AUEC, a parameter of interest for clinical comparability assessments consistent with the FDA draft guidance on clinical pharmacology data to support demonstration of biosimilarity 9.\n\nIn this study, an underlying imbalance in the rituximab‐EU and rituximab‐US groups was evident from baseline patient disease characteristics. To adequately characterise response profiles for each group, separate fixed‐effects were estimated for each reference group, in addition to inclusion of covariates to account for the imbalance. The aim was to evaluate whether treatment differences could be explained or predicted by the covariates through the imbalance between groups. Therefore, the simultaneous estimation approach was preferable to forward selection of covariates which may introduce bias in the estimated values 30, 31. Incorporation of covariates in the models assuming a pooled rituximab‐EU/US population (data not shown) did not account for all the imbalance, indicating unmeasured covariates also may have contributed to the underlying imbalance. In addition to the pooling approach, an attempt to incorporate group‐specific random effects to provide correlation within the groups was conducted. This confirmed that it was not possible to estimate a precise between‐group variability term with the small number of groups to characterise the remaining difference between the two reference products after inclusion of covariates in the model. As may be expected, comparative assessments between two reference products conducted with fixed effects resulted in an asymmetric comparison. That is, the distribution of mean estimated differences between two reference products is shifted, resulting in a nonzero mean. Details of this particular finding, while insightful, may not be easily understood without evaluation of simulation of various hypothetical scenarios. An alternative perspective, which is included in our analysis, was to evaluate each assessment using absolute difference. Since the emphasis of similarity is on the magnitude of difference, the absolute difference is consistent with the objectives of the given analysis and offered an intuitive interpretation of the analysis results. Lastly, imbalances in baseline disease characteristics, which tend to occur in PK trial settings, can be addressed to a great extent in the mixed‐effect modelling framework through a typical covariate analysis. In this regard, the models developed in this analysis included the individual components of baseline disease activity and elucidated potential confounding factors. In particular, the ACR model indicated that patients with a higher swollen joint count had a higher probability of being an ACR responder, while those with a higher tender joint count had a lower probability. As others have described, joint tenderness might indicate chronification of the pain reaction rather than ongoing inflammation and could therefore be a confounding factor 32. That is, a disconnection between the number of swollen and tender joints may appear in RA patients who have developed widespread pain syndromes or other hyperalgesic conditions 32 and consequently could result in somewhat different populations with respect to their potential to respond to treatment.\n\nStill, as found in this analysis, there may be unaccounted imbalances in the data presumably due largely to the randomization with small sample sizes and no stratification based on disease activity. In verifying this, an orthogonal approach using case–control analysis to match patients based on one or more variables may be useful, as described for an exposure–response analysis 33. This approach is often used to account for imbalance in nonrandomised studies and typically with much larger sample sizes. Applied here, this approach helped identify two important measures of disease activity, swollen joint count and patient's assessment of pain, which, when used for matching, resulted in balanced baseline disease activity among treatment groups. The resulting balanced groups all had similar clinical response profiles.\n\nIn conclusion, no point estimates of mean differences were found outside the reference ranges for either DAS28 or ACR20 scores. Furthermore, the estimated probabilities that the predicted differences for the given comparisons, PF‐05280586 vs. rituximab‐EU or PF‐05280586 vs. rituximab‐US, lie outside the boundaries of the respective reference ranges of absolute differences are low. Our analysis provided a case study where a model‐based PK/PD approach was utilised for biosimilarity assessment using clinical response data from the PK similarly study comparing a proposed biosimilar against two reference products. The results may therefore be used as a PK/PD demonstration of no clinically meaningful differences in support of overall biosimilarity determination. This case study offers an example for additional applications of clinical pharmacology studies and approaches aimed for efficient biosimilar development that are essential for improving patient access to the important, often lifesaving, biologic therapies.\n\nCompeting Interests\nAll authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (http://www.icmje.org/coi_disclosure.pdf) (available on request from the corresponding author) and declare the following financial relationships with organizations that might have an interest in the submitted work in the previous 3 years: BG, LAM, DY, RL and XM are employees of Pfizer Inc., JHW, MLZ, and GSG were employees of Pfizer Inc at the time of the study, MMH and J‐CB were paid consultants of Pfizer Inc.\n\n\nWe acknowledge the investigators and patients who contributed to this study. We thank Jian Du, Dian Xu and Stuart Pearce for preparation of NONMEM datasets. We thank Michael Amantea for helpful advice. This study was funded by Pfizer Inc. Editorial assistance was provided by Christina McManus, PhD, of Engage Scientific Solutions and funded by Pfizer.\n\nContributors\nJHW and XM designed the research. J‐CB, BG, LAM, GSG, DY, RL, JHW, MMH, MLZ, K‐HL and XM performed the research. MMH, JHW, MLZ, K‐HL and XM analysed the data. JHW and XM wrote the manuscript.\n\nSupporting information\n\nTable S1 Parameter estimates for Disease Activity Score in 28 Joints change from baseline and American College of Rheumatology responder rate models.\n\n\nTable S2 Patient demographics and baseline disease characteristics for the pharmacokinetic/pharmacodynamic modelling analysis population before and after propensity score matching.\n\n\nFigure S1 Visual predictive check of the rituximab pharmacokinetic model.\n\n\nFigure S2 Comparative assessment between PF‐05280586 and two rituximab comparators for ACR50 and ACR70 responder rates normalised area under effect curves.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n\n Supporting info item\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nSouthan \nC \n, \nSharman \nJL \n, \nBenson \nHE \n, \nFaccenda \nE \n, \nPawson \nAJ \n, \nAlexander \nSP \n, et al.\nThe IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands . 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Population Approach Group in Europe (PAGE), 2011 Available at http://www.page‐meeting.org/?abstract=2229 (last accessed 6 June 2016).\n31 \n\nHarrell \nFE \n. Regression modeling strategies: With applications to linear models, logistic regression, and survival analysis , 2nd edn. New York : Springer International Publishing , 2010 .\n32 \n\nKristensen \nLE \n, \nBliddal \nH \n, \nChristensen \nR \n, \nKarlsson \nJA \n, \nGulfe \nA \n, \nSaxne \nT \n, et al.\nIs swollen to tender joint count ratio a new and useful clinical marker for biologic drug response in rheumatoid arthritis? Results from a Swedish cohort . Arthritis Care Res (Hoboken) \n2014 ; 66 : 173 –179 .23982986 \n33 \n\nYang \nJ \n, \nZhao \nH \n, \nGarnett \nC \n, \nRahman \nA \n, \nGobburu \nJV \n, \nPierce \nW \n, et al.\nThe combination of exposure‐response and case–control analyses in regulatory decision making . J Clin Pharmacol \n2013 ; 53 : 160 –166 .23436261\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0306-5251", "issue": "82(6)", "journal": "British journal of clinical pharmacology", "keywords": "Biosimilar; pharmacodynamics; pharmacokinetics", "medline_ta": "Br J Clin Pharmacol", "mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "7503323", "other_id": null, "pages": "1568-1579", "pmc": null, "pmid": "27530379", "pubdate": "2016-12", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "17127262;23982986;18571968;23436261;27530379;25353186;26909489;20488885;19626001;22048227;1575785;23436260;15951469;22318617;26650438;15201414;16947627;18058203;20635122;16649186;20699241;26464438", "title": "Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab.", "title_normalized": "comparative assessment of clinical response in patients with rheumatoid arthritis between pf 05280586 a proposed rituximab biosimilar and rituximab" }

[ { "companynumb": "MX-ROCHE-1410426", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": "20130416", "drugenddateformat": "102", "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130416", "drugstartdateformat": "102", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" } ], "patientagegroup": null, "patientonsetage": "20", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "77.5", "reaction": [ { "reactionmeddrapt": "Thrombocytopenic purpura", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130428" } }, "primarysource": { "literaturereference": ", HUTMACHER M, ZIERHUT M, BECKER J-C, GUMBINER B, SPENCER-GREEN G, MELIA L, LIAO K-H, SUSTER M, YIN D, LI R AND MENG X. COMPARATIVE ASSESSMENT OF CLINICAL RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS BETWEEN PF-05280586, A PROPOSED RITUXIMAB BIOSIMILAR, AND RITUXIMAB. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2016;:1-12.", "literaturereference_normalized": "comparative assessment of clinical response in patients with rheumatoid arthritis between pf 05280586 a proposed rituximab biosimilar and rituximab", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20161004", "receivedate": "20140821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10397728, "safetyreportversion": 7, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170206" } ]

{ "abstract": "Amiodarone is a common antiarrhythmic drug that is utilised in clinical practice and is associated with pulmonary toxicity. The most common form of pulmonary complication is interstitial pneumonitis which is treated with discontinuation of amiodarone and initiation of corticosteroids. Amiodarone-induced pulmonary eosinophilia is a rare complication of amiodarone therapy, with blood and pulmonary eosinophilia the predominant features. During the COVID-19 era, the incidence of delay in treatment of pulmonary pathology is also delayed due to the effort of excluding COVID-19 infection. Here we report a case of a 64-year-old man who developed eosinophilic pneumonia after initiation of amiodarone therapy, and the investigations required to exclude other forms of pulmonary toxicity. We also reviewed the effect of COVID-19 testing in the management of patients presenting with respiratory distress.", "affiliations": "Department of Cardiology, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.;Department of Respiratory Medicine, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.;Department of Cardiology, Epworth Healthcare, Melbourne, 3121 Victoria, Australia.", "authors": "Azraai|Meor|M|;McMahon|Marcus|M|;Dick|Ronald|R|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone", "country": "United States", "delete": false, "doi": "10.31083/j.rcm.2021.01.267", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-6550", "issue": "22(1)", "journal": "Reviews in cardiovascular medicine", "keywords": "Amiodarone; Amiodarone-induced pulmonary toxicity; COVID-19; Corticosteroids; Pulmonary eosinophilia", "medline_ta": "Rev Cardiovasc Med", "mesh_terms": "D000542:Alveolitis, Extrinsic Allergic; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000086382:COVID-19; D000086742:COVID-19 Testing; D057210:Delayed Diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "100960007", "other_id": null, "pages": "181-184", "pmc": null, "pmid": "33792260", "pubdate": "2021-03-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Case report of amiodarone-associated allergic pneumonitis amidst the COVID-19 pandemic.", "title_normalized": "case report of amiodarone associated allergic pneumonitis amidst the covid 19 pandemic" }

[ { "companynumb": "AU-MYLANLABS-2021M1039380", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Atrial fibrillation", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": "076217", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "1200 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Atrial fibrillation", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eosinophilic pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory fatigue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Azraai M, McMahon M, Dick R. Case report of amiodarone-associated allergic pneumonitis amidst the COVID-19 pandemic. Rev-Cardiovasc-Med 2021;22(1):181-184.", "literaturereference_normalized": "case report of amiodarone associated allergic pneumonitis amidst the covid 19 pandemic", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220303", "receivedate": "20210708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19506954, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "A 74-year-old woman with a week-long history of cold symptoms was diagnosed with Lemierre syndrome that involved her left external jugular vein.\n\n\n\nThe patient was successfully treated with 4 weeks of antibiotics and anticoagulant treatment. Typical cases of Lemierre syndrome involve only the internal jugular vein. The external jugular vein is anatomically distant from the pharyngolaryngeal space and usually does not receive blood or lymphatic flow from there. Thus, Lemierre syndrome ordinarily does not involve the external jugular vein and clinical characteristics of external jugular vein-involving Lemierre syndrome have not been uncovered, mainly due to its rarity. Based on our review, it would not much differ from those of typical cases.\n\n\n\nConsidering the potential severity and mortality, more attention should be paid to this potentially fatal disease that may demonstrate atypical manifestation, as shown in this case. Accumulation of cases would be needed for further understanding.", "affiliations": "Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyama Okayama Japan.;Department of Pharmacy Tsuyama Central Hospital Tsuyama Okayama Japan.;Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyama Okayama Japan.", "authors": "Hagiya|Hideharu|H|;Haruki|Yuto|Y|;Otsuka|Fumio|F|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/ams2.61", "fulltext": null, "fulltext_license": null, "issn_linking": "2052-8817", "issue": "2(1)", "journal": "Acute medicine & surgery", "keywords": "External jugular vein (EJV); Fusobacterium; Lemierre syndrome; jugular vein suppurative thrombophlebitis; septic pulmonary emboli (SPE)", "medline_ta": "Acute Med Surg", "mesh_terms": null, "nlm_unique_id": "101635464", "other_id": null, "pages": "64-68", "pmc": null, "pmid": "29123694", "pubdate": "2015-01", "publication_types": "D002363:Case Reports", "references": "17308690;10371324;16020900;12441902;9796654;464215;15192164;10326820;24436600;18330604", "title": "Lemierre syndrome involving external jugular vein.", "title_normalized": "lemierre syndrome involving external jugular vein" }

[ { "companynumb": "JP-TEVA-2017-JP-836089", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "89081", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSES, 3 G EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUSOBACTERIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN/SULBACTAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypercoagulation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lemierre syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Glucose tolerance impaired", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Laryngeal inflammation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA H, HARUKI Y, OTSUKA F. LEMIERRE SYNDROME INVOLVING EXTERNAL JUGULAR VEIN. ACUTE-MED-SURG 2015?2(1):64-68.", "literaturereference_normalized": "lemierre syndrome involving external jugular vein", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180107", "receivedate": "20171227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14329454, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "JP-MYLANLABS-2017M1078035", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SINGLE DOSES, 3 G EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUSOBACTERIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPI BIS PLUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypercoagulation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lemierre syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephritis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Glucose tolerance impaired", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Laryngeal inflammation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HAGIYA H, HARUKI Y, OTSUKA F. LEMIERRE SYNDROME INVOLVING EXTERNAL JUGULAR VEIN. ACUTE-MED-SURG 2015;2(1):64-68.. 2015;2(1):64-68", "literaturereference_normalized": "lemierre syndrome involving external jugular vein", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171221", "receivedate": "20171221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14314939, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "OBJECTIVE\nTo assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies.\n\n\nMETHODS\nRetrospective single-centre study of 25 patients with refractory TAK.\n\n\nRESULTS\nPatients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2-84)) and 9 with ETA (median 28 months (range 4-82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer.\n\n\nCONCLUSIONS\nIn this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.", "affiliations": "Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH 44106, USA. molloye@ccf.org", "authors": "Molloy|E S|ES|;Langford|C A|CA|;Clark|T M|TM|;Gota|C E|CE|;Hoffman|G S|GS|", "chemical_list": "D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1136/ard.2008.093260", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4967", "issue": "67(11)", "journal": "Annals of the rheumatic diseases", "keywords": null, "medline_ta": "Ann Rheum Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D018124:Receptors, Tumor Necrosis Factor; D012008:Recurrence; D012189:Retrospective Studies; D013625:Takayasu Arteritis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0372355", "other_id": null, "pages": "1567-9", "pmc": null, "pmid": "18677012", "pubdate": "2008-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up.", "title_normalized": "anti tumour necrosis factor therapy in patients with refractory takayasu arteritis long term follow up" }

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ANTI-TUMOUR NECROSIS FACTOR THERAPY IN PATIENTS WITH REFRACTORY TAKAYASU ARTERITIS: LONG-TERM FOLLOW-UP. 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ANTI-TUMOUR NECROSIS FACTOR THERAPY IN PATIENTS WITH REFRACTORY TAKAYASU ARTERITIS: LONG-TERM FOLLOW-UP. ANN RHEUM DIS 2008;67:1567-1569.", "literaturereference_normalized": "anti tumour necrosis factor therapy in patients with refractory takayasu arteritis long term follow up", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170530", "receivedate": "20170530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13592698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "BACKGROUND\nThe development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good's syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.\n\n\nMETHODS\nA 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.\n\n\nCONCLUSIONS\nIt is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.", "affiliations": "Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan. lacote19thg@gmail.com.;Department of Thoracic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.", "authors": "Ueno|Tatsuya|T|http://orcid.org/0000-0002-6212-0265;Sato|Nobuyuki|N|;Kon|Tomoya|T|;Haga|Rie|R|;Nunomura|Jin-Ichi|JI|;Nakamichi|Kazuo|K|;Saijo|Masayuki|M|;Tomiyama|Masahiko|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-018-1041-4", "fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 104110.1186/s12883-018-1041-4Case ReportProgressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review http://orcid.org/0000-0002-6212-0265Ueno Tatsuya +81 17 726 8111lacote19thg@gmail.comtatsuya_ueno@med.pref.aomori.jp 1Sato Nobuyuki nobuyuki_sato@med.pref.aomori.jp 2Kon Tomoya tk10608pc@nifty.com 1Haga Rie rie_haga@med.pref.aomori.jp 1Nunomura Jin-ichi Jin-ichi_Nunomura@med.pref.aomori.jp 1Nakamichi Kazuo nakamich@nih.go.jp 3Saijo Masayuki masaijo@nih.go.jp 3Tomiyama Masahiko masahiko_tomiyama@med.pref.aomori.jp 11 0000 0004 0378 7152grid.413825.9Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551 Japan 2 0000 0004 0378 7152grid.413825.9Department of Thoracic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan 3 0000 0001 2220 1880grid.410795.eDepartment of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan 10 4 2018 10 4 2018 2018 18 3721 11 2017 27 3 2018 © The Author(s). 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good’s syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.\n\nCase presentation:\nA 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.\n\nConclusions\nIt is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.\n\nKeywords\nProgressive multifocal leukoencephalopathyGood’s syndromeMyasthenia gravisThymomaImmunodeficiencyJC virushttp://dx.doi.org/10.13039/501100001691Japan Society for the Promotion of Science17K09768Nakamichi Kazuo http://dx.doi.org/10.13039/501100003478Ministry of Health, Labour and WelfareH29-Nanchitou (Nan)-Ippan-036Saijo Masayuki issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nProgressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus (JCV) [1]. The development of PML is associated with severe cellular immunosuppression e.g., human immunodeficiency virus (HIV) infection, and immunosuppressive therapy, including natalizumab and other monoclonal antibodies, fingolimod, and dimethyl fumarate [2].\n\nPatients with thymoma often also have an autoimmune disease, such as myasthenia gravis (MG) [3]. Good’s syndrome (GS), also referred to as thymoma with immunodeficiency, is a rare immunodeficiency syndrome related to thymoma, characterized by hypogammaglobulinemia, low or absent B cells, CD4+ lymphopenia, and reversal of the CD4/CD8 ratio [4, 5]. GS thus involves not only humoral, also cellular immunosuppression [4, 5]. The incidence of hypogammaglobulinemia in patients with thymoma is 6%–11%, while GS occurs in 7% of patients with primary antibody deficiency referred to a chest clinic, and is the underlying cause of immunodeficiency in 1%–2% of patients with primary antibody deficiency receiving immunoglobulin replacement therapy [4, 6]. MG has been identified in 9.1%–15.7% of patients with GS [4, 5].\n\nTo the best of our knowledge, eight cases of PML with thymoma have been reported in the literature (Table 1) [7–14], though GS was confirmed in only three of these eight cases [11, 12, 14]. In the case of PML related to thymoma, it may be difficult to judge if the immunodeficiency is caused by chemotherapy for the thymoma, by GS caused by the thymoma itself, by immunosuppressive therapy for MG, or by a combination of these. The neurological symptoms improved in one patient with PML related to immunosuppressive therapy for MG, complicated with thymoma, following a reduction of immunotherapy for PML (Table 1) [10]. It is therefore important to identify the cause of the immunodeficiency responsible for PML, to enable the development of an appropriate treatment strategy. We herein report a patient with invasive thymoma who developed PML, who also had chemotherapy-induced immunodeficiency and GS due to an invasive thymoma.Table 1 Clinical features of patients with progressive multifocal leukoencephalopathy related to thymoma\n\nReference\tAge\tSex\tCauses of immunodeficiency\tTime\tTreatment ofthymoma\tJC virus\nin the CSF\tCD19+ B cell\n(cells/μL)\tCD4/CD8\tCD4+ T cell\n(cells/μL)\tCD8+ T cell\n(cells/μL)\tIg level\n(mg/dL)\tPML\nTreatment\tPrognosis\tSurvival\nperiod\t\n[14]\t65\tF\tGood’s syndrome\t0\tSR\t>1million\ncopies/mL\tNo detectable\t0.66\n(1.13–3.93)\tNR\tNR\tIgG: 570 (670–1450)\nIgA: 22 (88–450)\nIgM: 22 (27–210)\tMirtazapine\nMefloquine\tDeath\tProbably\n5–6 M\t\n[13]\t39\tM\tChemotherapy for thymoma\t10 Y\tSR + CT\t9,200\ngEq/μL\t1 (100–800)\t0.2\n(0.9–2.8)\t19\n(450–1500)\t113\n(250–1000)\tNR\tCidofovir\tDeath\tNR\t\n[12]\t79\tF\tGood’s syndrome\t8 Y\tSR\t9,258\npairs/mL\tAbsent\t1.5\t648\t425\tIgG: 619 (700–1600)\nIgA: <25 (70–400)\nIgM: <18 (40–250)\tCidofovir\tDeath\t5 M\t\n[11]\t58\tM\tGood’s syndrome\t5 M\tSR\t810\ncopies/mL\tNR\t0.6\n(0.8–2.4)\tNR\tNR\tIgM: 31 (40–300)\tCidofovir\nRisperidone\nIVIg\tAlive\tAt least 11 M\t\n[10]\t44\tF\tImmunosuppressive therapy for MG\t2 M\tSR\tPositive\tNR\tNR\tNR\tNR\tNR\tReduction of immunotherapy\tAlive\tAt least 19 M\t\n[9]\t58\tM\tChemotherapy\nGood’s syndrome?\t9 Y\tRT + CT\tNR\tNR\tNR\tNR\tNR\tNR\tCytrabine\tDeath\t13 W\t\n[8]\t41\tF\tImmunosuppressive therapy for MG\t29 Y\tRT + SR\tNR\tNR\tNR\tNR\tNR\tNR\tReduction of immunotherapy\tDeath\t6 W\t\n[7]\t39\tF\tImmunosuppressive therapy for MG\nGood’s syndrome?\t3 Y\tRT\tNR\tNR\tNR\tNR\tNR\tNR\tNone\tDeath\t5 M\t\nPresent case\t47\tF\tGood’s syndrome\nChemotherapy\t23 Y\tRT + SR + CT\t6,283,000\ncopies/mL\t3\t0.6\t11\t19\tIgG: 282 (870–1700)\nIgA: 58 (110–410)\nIgM: 15 (35–220)\tMirtazapine\nMefloquine\nIVIg\tDeath\t3 M\t\nTime = period from the diagnosis of thymoma to the onset of PML. Numbers in parentheses indicate the reference range. Patients in references [9, 10] survived for at least 11 and 19 months, respectively, but their subsequent prognosis was unknown. Abbreviations. CSF: cerebrospinal fluid; CT: chemotherapy; IVIg: intravenous immunoglobulin; M: months; MG: myasthenia gravis; NR: not reported; PML: progressive multifocal leukoencephalopathy; RT: radiation therapy; SR: surgical resection; W: weeks; Y: years\n\n\n\nCase presentation\nA 47-year-old Japanese woman with aphasia and gait difficulty was admitted for the evaluation of a brain magnetic resonance imaging (MRI) abnormality. She had gradually developed aphasia and gait difficulty 2 months before admission. Her medical history included an invasive thymoma diagnosed at 24 years old, MG (Myasthenia Gravis Foundation of America clinical classification IIa) at 35 years old, cryptococcal meningoencephalitis at 36 years old, and erythrodermic psoriasis at 46 years old. The time course of her medical history and treatments are shown in Fig. 1. Ptosis and limb weakness, as MG symptoms, had completely recovered. She demonstrated chemotherapy-induced immunosuppression, and the invasive thymoma (Masaoka stage IVB) was refractory to shrinkage by multiple chemotherapies. The invasive thymoma had also seeded intraperitoneally. She had received her last chemotherapy (cyclophosphamide, 500 mg; doxorubicin, 50 mg; cisplatin, 50 mg) 16 months before admission, and had been taking prednisolone (12.5 mg/day) from 44 years of age. Her family history was unremarkable.Fig. 1 Medical history and treatment course. ADR: adriamycin; CBDCA: carboplatin; CDDP: cisplatin; CM: cryptococcal meningoencephalitis; CPA: cyclophosphamide; DOX: doxorubicin; EP: erythrodermic psoriasis; MG: myasthenia gravis; PTX: paclitaxel; PSL: prednisolone; RT: radiation therapy; S-1: tegafur/gimeracil/oteracil potassium; SR: surgical resection of thymoma; VCR: vincristine; VDS: vindesine\n\n\n\nOn admission, her body weight was 39.5 kg and she was 151.7 cm tall (body mass index of 17.2 kg/m2). Her vital signs were normal and her Glasgow coma scale score was 12 (E4V2M6). Physical examination revealed widespread erythema with scaling and exfoliation of the skin due to erythrodermic psoriasis, and an invasive thymoma in the left lower chest wall. She had a central venous port for chemotherapy in her left upper chest wall. Neurological examination revealed motor aphasia and central facial weakness on the right side. Barré’s sign for the upper extremities and Mingazzini’s sign for the lower extremities were negative. Finger-to-nose and heel-to-knee tests demonstrated no abnormalities. Bilateral deep tendon reflexes were normal, but bilateral plantar responses were extensor.\n\nLaboratory studies showed the following results: hematocrit, 32.6%; hemoglobin, 10.7 g/dL; red blood cell count, 3.74 × 106/μL; mean corpuscular volume, 87.1 fL; platelet count, 22.7 × 104/μL; and white blood cell count, 8.2 × 103/μL, with 0.9% lymphocytes (74 cells/μL). Lymphocyte subgroups were as follows: CD4, 14.9% (normal range 25.0%–54.0%); CD8, 25.0% (normal range 2.0%–56.0%); CD4/CD8 ratio, 0.6; CD19, 0.4% (normal range 5.0%–24.0%); and CD20, 1.1% (normal range 3.0%–20.0%). Her total IgG level was 282 mg/dL (normal range 870–1700 mg/dL), IgA level was 58 mg/dL (normal range 110–410 mg/dL), and IgM level was 15 mg/dL (normal range 35–220 mg/dL). Serology for HIV type 1/2, human T-lymphotropic virus type 1, Candida, Aspergillus, Toxoplasma, and Mycobacterium tuberculosis were all negative. Anti-acetylcholine receptor (AchR) antibodies were positive (0.4 nmol/L: normal range < 0.3 nmol/L). Cerebrospinal fluid (CSF) analysis revealed a normal cell count, protein, and glucose, but an elevated IgG index (1.1) and elevated myelin basic protein levels (238 pg/mL). Oligoclonal bands and CSF cytology were negative. CSF cultures for bacteria, fungi, and M. tuberculosis were negative. CSF polymerase chain reaction (PCR) tests for M. tuberculosis, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus were all negative, but CSF real-time PCR for JCV was positive, showing 6,283,000 copies/mL. Brain MRI showed hyperintense lesions in the left frontal white matter on T2-weighted images and fluid-attenuated inversion recovery images (Fig. 2a, b). These lesions were hypointense without contrast enhancement on T1-weighted images (Fig. 2c, d). Diffusion-weighted images (DWI) demonstrated a hyperintense lesion in the margin of left frontal white matter (Fig. 2e). Arterial spin labeling revealed hyperperfusion in the DWI hyperintense lesion (Fig. 2f). Magnetic resonance spectroscopy showed a decrease in N-acetylaspartate and increased lactate in the lesions (Fig. 3). Thallium-201 single photon emission computed tomography revealed no uptake in the lesions (Fig. 4). Based on the results of clinical features, imaging findings, and CSF PCR for JCV, the patient was finally diagnosed with non-HIV-related PML due to chemotherapy-induced immunodeficiency and GS [4, 15].Fig. 2 Brain magnetic resonance imaging on admission (a-e) and at 30 days after admission (f). T2-weighted images (a) and fluid-attenuated inversion recovery images (b) show hyperintense lesions in the left frontal white matter. These lesions were hypointense on T1-weighted images (c). There was no enhancement on gadolinium-enhanced T1-weighted images (d). Diffusion-weighted images (DWI) demonstrated a hyperintense lesion in the margin of the left frontal white matter (e). Arterial spin labeling revealed hyperperfusion in the DWI hyperintense lesion (f)\n\nFig. 3 Magnetic resonance spectroscopy (MRS) and diffusion-weighted images (DWI) at 30 days after admission. Representative locations selected for MRS (a). MRS showed a decrease in N-acetylaspartate and increased lactate in the DWI hyperintense lesion (b, c)\n\nFig. 4 Thallium-201 single photon emission computed tomography at 11 days after admission. Early (a) and delayed (b) scans demonstrated no uptake in the lesions\n\n\n\nMonthly intravenous immunoglobulin (IVIg) therapy for hypogammaglobulinemia was started 10 days after admission. After the diagnosis of non-HIV-related PML, mirtazapine 15 mg/day was started 24 days after admission, and oral mefloquine 275 mg/day was also started for 3 days on day 25, followed by 275 mg once weekly. We also tapered her prednisolone to 10 mg/day on day 44. She had no deterioration of neurological symptoms indicating immune reconstitution inflammatory syndrome. However, she developed central venous port-related infections with no improvement of neurological symptoms, and received antibiotic and antifungal treatments on day 39. Although we tried to remove the central venous port, it could not be withdrawn without a risk of vascular injury. The above treatments were continued, but the patient unfortunately died of sepsis due to Candida albicans and Staphylococcus epidermis, as determined by blood culture on day 46.\n\nDiscussion and conclusions\nWe present a patient with invasive thymoma-associated PML who also had chemotherapy-induced immunodeficiency and GS due to the invasive thymoma. This case demonstrates two important points: (1) it is necessary to consider the possibility of GS in patients with PML related to thymoma; and (2) neurologists should keep in mind the risk of PML in MG patients with thymoma, even if their MG symptoms are in remission.\n\nAccording to our literature review, the possible causes of immunodeficiency in patients with thymoma-related PML include GS, chemotherapy-induced immunodeficiency, and immunosuppressive therapy for MG (Table 1). Our patient had CD4+, CD8+, and CD19+ lymphopenia, and hypogammaglobulinemia, which are characteristics of GS [4, 5]. These results suggest that this patient had GS. GS with PML has been reported in three previous cases, none of whom received chemotherapy for thymoma [11, 12, 14]; however, our patient had received repeated chemotherapy for invasive thymoma (Table 1). We were unable to judge if another two cases had GS, because their immunological statuses were not reported [7, 8]. Chemotherapeutic agents, such as cyclophosphamide, doxorubicin, vincristine, and methotrexate, can cause lymphopenia, including decreases in CD19+ B cells, CD4+ and CD8+ T cells, and decreased IgM levels with normal IgG levels [16]. The recovery periods for B cells and CD8+ T cells after chemotherapy are 1–3 months and 3–6 months, respectively [17–19]. The recovery of CD4+ T cells 6 months after completion of cytotoxic chemotherapy is inversely related to age for children younger than approximately 15 years, whereas persistent depletion is observed in older patients [20]. Given that a year had passed after the last chemotherapy in the current case, it was possible that her B and CD8+ T cells might have recovered, but that was not the case, while all immunoglobulin subclasses were also decreased. The patient’s age suggests that the decrease of CD4+ T cells may have been caused by her chemotherapy. There are currently no established diagnostic criteria or specific biomarkers for GS, and it is diagnosed on the basis of the existence of thymoma, hypogammaglobulinemia, low or absent B cells, CD4+ lymphopenia, and reversal of the CD4/CD8 ratio [4, 5]. Our patient with invasive thymoma had decreased B and CD8+ T cells, and hypogammaglobulinemia, even after considering chemotherapy, and we therefore considered the possibility of GS in addition to chemotherapy-induced immunodeficiency, resulting in severe humoral and cellular immunosuppression. To the best of our knowledge, this is the first reported case of PML with concurrent MG and GS against a background of thymoma. It is therefore necessary to judge patients with various possible causes of immunodeficiency, including chemotherapy, comprehensively, rather than assuming that chemotherapy-induced immunodeficiency is the cause.\n\nThere have been two reported cases of comorbid PML with MG (Table 1), neither of whom received chemotherapy. There was no description of any lymphopenia or hypogammaglobulinemia [8, 10] (Table 1), but their MG symptoms were presumably severe, because they received high-dose prednisolone and azathioprine for symptom control [8, 10]. It is therefore possible that this immunosuppressive therapy may have triggered the onset of PML. We were unable to judge if these two cases had GS. In the current case, PML occurred even when MG was in remission. However, this patient had severe humoral and cellular immunosuppression, and her MG symptoms may thus have improved. Neurologists should therefore consider the possibility of PML in patients with MG related to thymoma who experience progressive exacerbation of neurological symptoms, regardless of the severity of MG symptoms, and should evaluate the patient’s immunological status accordingly, including complete blood count, quantitative immunoglobulins, and B cell/T cell subsets. Regarding the need for immunological evaluations of MG patients without thymoma at the initial presentation, it is advisable to evaluate the immunological status of such patients if their neurological symptoms or anti-AchR antibody values deteriorate, given that a thymoma may be detected subsequently [21].\n\nIt is also necessary to consider treating GS to prevent the development of PML; however, this is challenging because there is currently no established treatment for GS [6], though thymectomy, radiotherapy, combination chemotherapy, immunosuppressive therapy, plasmapheresis, and splenectomy are all possible treatment options [4]. Squintani et al. reported on a patient with PML who had normal CD4+ and CD8+ T cells and hypogammaglobulinemia, indicating humoral but not cellular immunodeficiency [12]. Because PML is associated with severe cellular immunosuppression [2], hypogammaglobulinemia itself does not usually result in reactivation of JCV. Although Squintani et al.’s case might also have had cellular immunodeficiency, treatment of GS-related hypogammaglobulinemia by immunoglobulin replacement therapy may be considered for PML prevention.\n\nThe reported period from the diagnosis of thymoma to the onset of PML is 0–29 years (Table 1). Two patients with relatively short periods from thymoma diagnosis to PML onset survived [10, 11], including one patient with MG who received a reduction of immunotherapy for PML [10], and a patient with GS who received cidofovir and risperidone for PML and IVIg for GS [11]. No quantitative analyses were performed in the patient with MG [10], but the patient with GS had a low JCV level (810 copies/mL) [11]. In the case of thymoma diagnosis with simultaneous onset of PML, the patient with GS had a high JCV level (> 1 × 106 copies/mL) and was treated with mirtazapine and mefloquine, but probably died within 5–6 months [14]. Patients with a low CSF JCV level were found to survive longer than patients with a higher JCV level [22], though the median survival of patients with non-HIV-related PML was only 3 months [23]. In the current case, the period from thymoma diagnosis to PML onset was 24 years. This patient had a high JCV level (6,283,000 copies/mL) and received mirtazapine, mefloquine, and IVIg, but died of sepsis after 3 months. JCV levels may thus be a better prognostic marker than time from thymoma diagnosis to PML onset in patients with PML related to thymoma; however, the rarity of reported cases means that this possibility needs to be evaluated in other cases.\n\nIn summary, we present a patient with invasive thymoma-associated PML who also had chemotherapy-induced immunodeficiency and GS due to thymoma. This case highlights the need to consider the possibility of immunodeficiency caused by to GS in patients with PML related to thymoma. Furthermore, physicians should keep in mind the risk of PML in MG patients with thymoma, even if their MG symptoms are in remission, and should evaluate the immunological status of the patients accordingly.\n\nAbbreviations\nADRAdriamycin\n\nCBDCACarboplatin\n\nCDDPCisplatin\n\nCMCryptococcal meningoencephalitis\n\nCPACyclophosphamide\n\nCSFCerebrospinal fluid\n\nCTChemotherapy\n\nDOXDoxorubicin\n\nDWIDiffusion-weighted images\n\nEPErythrodermic psoriasis\n\nGSGood’s syndrome\n\nHIVHuman immunodeficiency virus\n\nJCVJC virus\n\nMMonths\n\nMGMyasthenia gravis\n\nMRIMagnetic resonance imaging\n\nNRNot reported\n\nPCRPolymerase chain reaction\n\nPMLProgressive multifocal leukoencephalopathy\n\nPSLPrednisolone\n\nPTXPaclitaxel\n\nRTRadiation therapy\n\nS-1Tegafur/gimeracil/oteracil potassium\n\nSRSurgical resection of thymoma\n\nVCRVincristine\n\nVDSVindesine\n\nWWeeks\n\nYYears\n\nAcknowledgements\nWe thank Yoshiharu Miura, Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan, for advice on PML treatment, and Ann Turnley, PhD, from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.\n\nFunding\nThis work was partly supported by JSPS KAKENHI (Grant Number 17 K09768) and by a Grant-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan (Grant Number H29-Nanchitou [Nan]-Ippan-036).\n\nAvailability of data and materials\nAll data containing relevant information to support the study findings are included in the manuscript.\n\nAuthors’ contributions\nTU, NS, TK, RH, and JN collected the clinical data and interpreted the data. TU drafted the manuscript. KN and MS performed CSF real-time PCR for JCV. NS, TK, RH, JN, KN, MS, and MT helped write and revise the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe authors declare that ethics approval was not required for this case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s father for publication of this case report and any accompanying images. A copy of the written consent is available for review by the series editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Ann Neurol 2006 60 2 162 173 10.1002/ana.20933 16862584\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "18(1)", "journal": "BMC neurology", "keywords": "Good’s syndrome; Immunodeficiency; JC virus; Myasthenia gravis; Progressive multifocal leukoencephalopathy; Thymoma", "medline_ta": "BMC Neurol", "mesh_terms": "D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008875:Middle Aged; D009157:Myasthenia Gravis; D013945:Thymoma; D013953:Thymus Neoplasms", "nlm_unique_id": "100968555", "other_id": null, "pages": "37", "pmc": null, "pmid": "29631544", "pubdate": "2018-04-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26408958;23897378;1628122;889304;19054676;27497628;7919339;23568998;20298966;3024005;19695918;7073259;23857613;10360779;16862584;28245526;23509314;7800006;20149753;12499426;9160675;20561807;1698484", "title": "Progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review.", "title_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review" }

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. 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"drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "39.5", "reaction": [ { "reactionmeddrapt": "Good syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Secondary immunodeficiency", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, SATO N, KON T, HAGA R, NUNOMURA J, NAKAMICHI K ET 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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN (IMMUNOGLOBULIN HUMAN NORMAL)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "THYMOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MEFLOQUINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "275 MG, 1 /WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "275", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEFLOQUINE" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "40", "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Vascular access site infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO T, SATO N, KON T, HAGA R, NUNOMURA J, NAKAMICHI K ET AL.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. BMC NEUROLOGY. 2018?18(37):1-8", "literaturereference_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180427", "receivedate": "20180427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14821165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "JP-PFIZER INC-2018167792", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 UNK(TAPERED) ON DAY 44", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, UNK (HER LAST CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "THYMOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "39.5", "reaction": [ { "reactionmeddrapt": "Immunodeficiency", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UENO, T.. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ASSOCIATED WITH THYMOMA WITH IMMUNODEFICIENCY: A CASE REPORT AND LITERATURE REVIEW. BMC NEUROLOGY. 2018?18 (1):10.1186/S12883-018-1041-4", "literaturereference_normalized": "progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180608", "receivedate": "20180427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14821935, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "OBJECTIVE\nPatients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end-of-life care for patients with RRMM after TCE.\n\n\nMETHODS\nThe ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations.\n\n\nRESULTS\nThe survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE.\n\n\nCONCLUSIONS\nFindings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden.", "affiliations": "Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland. Electronic address: sujith.dhanasiri@bms.com.;Genesis Research, Newcastle, United Kingdom.;Genesis Research, Newcastle, United Kingdom.;Bristol Myers Squibb, Princeton, New Jersey, USA.;NYU Langone Health, New York, New York, USA.;Clinica Universidad de Navarra, Navarra, Spain.", "authors": "Dhanasiri|Sujith|S|;Hollier-Hann|Georgia|G|;Stothard|Catherine|C|;Dhanda|Devender S|DS|;Davies|Faith E|FE|;Rodriguez-Otero|Paula|P|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clinthera.2021.09.013", "fulltext": null, "fulltext_license": null, "issn_linking": "0149-2918", "issue": null, "journal": "Clinical therapeutics", "keywords": "cross-sectional survey; health care resource use; multiple myeloma; treatment pattern; triple-class exposed", "medline_ta": "Clin Ther", "mesh_terms": null, "nlm_unique_id": "7706726", "other_id": null, "pages": null, "pmc": null, "pmid": "34736769", "pubdate": "2021-11-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Treatment Patterns and Outcomes in Triple-Class Exposed Patients With Relapsed and Refractory Multiple Myeloma: Findings From the Multinational ITEMISE Study.", "title_normalized": "treatment patterns and outcomes in triple class exposed patients with relapsed and refractory multiple myeloma findings from the multinational itemise study" }

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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DARATUMUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ELOTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELOTUZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IXAZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IXAZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospitalisation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospice care", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Dhanasirl, S. Treatment Patterns and Outcomes in Triple-Class Exposed Patients With Relapsed and Refractory Multiple Myeloma: Findings From the Multinational ITEMISE Study. Clinical Therapeutics. 2021", "literaturereference_normalized": "treatment patterns and outcomes in triple class exposed patients with relapsed and refractory multiple myeloma findings from the multinational itemise study", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20211116", "receivedate": "20211116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20072813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "A case is reported of acute psychosis, including florid visual and tactile hallucinations, in an 18-year-old male after intravenous misuse of 60 mg of pseudoephedrine hydrochloride. The literature is reviewed for other cases of psychosis following pseudoephedrine use.", "affiliations": "St Cadoc's Hospital, Caerleon, Gwent NP61XQ, UK.", "authors": "Sullivan|G|G|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/026988119601000413", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-8811", "issue": "10(4)", "journal": "Journal of psychopharmacology (Oxford, England)", "keywords": null, "medline_ta": "J Psychopharmacol", "mesh_terms": null, "nlm_unique_id": "8907828", "other_id": null, "pages": "324-5", "pmc": null, "pmid": "22302983", "pubdate": "1996-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Acute psychosis following intravenous abuse of pseudoephedrine: a case report.", "title_normalized": "acute psychosis following intravenous abuse of pseudoephedrine a case report" }

[ { "companynumb": "GB-JNJFOC-199704-0086", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PSEUDOEPHEDRINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "999999", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PSEUDOEPHEDRINE HYDROCHLORIDE." } ], "patientagegroup": "4", "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute psychosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, tactile", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Visual impairment", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SULLIVAN G. ACUTE PSYCHOSIS FOLLOWING INTRAVENOUS ABUSE OF PSEUDOEPHEDRINE: A CASE REPORT. JOURNAL OF PSYCHOLOGY 01-JAN-1996?10:4:324-325. SULLIVAN G. ACUTE PSYCHOSIS FOLLOWING INTRAVENOUS ABUSE OF PSEUDOEPHEDRINE: A CASE REPORT.. JOURNAL OF PSYCHOPHARMACOLOGY 1996?10:4:(324-325).", "literaturereference_normalized": "acute psychosis following intravenous abuse of pseudoephedrine a case report", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180508", "receivedate": "20180508", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14862131, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "BACKGROUND\nRates of opioid overdose deaths are increasing in the United States, leading to intensified efforts to provide medication-assisted treatments for opioid use disorders. It is not clear what effect opioid agonist treatments (ie, the µ-opioid receptor full agonist methadone and the partial agonist buprenorphine) may have on respiratory function. However, sleep-disordered breathing has been documented in methadone maintenance pharmacotherapy, and there is emerging evidence for similar sleep-disordered breathing in buprenorphine and buprenorphine-naloxone maintenance treatment.\n\n\nOBJECTIVE\nTo provide further clinical evidence of sleep-disordered breathing emerging in the context of buprenorphine-naloxone maintenance pharmacotherapy.\n\n\nMETHODS\nThe authors report two additional cases of sleep-disordered breathing that developed in patients with severe opioid use disorders, treated successfully as outpatients with buprenorphine-naloxone maintenance. Both patients provided written consent for their clinical information to be included in this case report, and elements of their identities have been masked to provide confidentiality.\n\n\nRESULTS\nTwo adult female patients, who were stable in buprenorphine-naloxone maintenance treatment developed daytime sleepiness, were referred for evaluation and found to have sleep-disordered breathing. One patient's daytime sleepiness improved with reduction in both buprenorphine-naloxone and other sedating medications as well as initiation of a constant positive airway pressure (CPAP) device. However, the other patient could not tolerate decreases in buprenorphine-naloxone and/or CPAP initiation and her daytime sleepiness persisted.\n\n\nCONCLUSIONS\nBuprenorphine-naloxone maintenance treatment can be associated with sleep-disordered breathing. It can be difficult to differentiate the cause(s) of sleep-disordered breathing among the effects of buprenorphine-naloxone treatment itself, co-occurring conditions, such as obesity and cigarette smoking or other medications, or some combination thereof. Regardless of etiology, sleep-disordered breathing and its consequences present unique challenges to the patient in recovery from an opioid use disorder and therefore warrants careful evaluation and management.", "affiliations": "Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, University of California, San Francisco, San Francisco, California.;Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.;Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.", "authors": "DeVido|Jeffrey|J|;Connery|Hilary|H|;Hill|Kevin P|KP|", "chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1551-7489", "issue": "11(4)", "journal": "Journal of opioid management", "keywords": null, "medline_ta": "J Opioid Manag", "mesh_terms": "D000328:Adult; D002047:Buprenorphine; D003937:Diagnosis, Differential; D019468:Disease Management; D005260:Female; D006801:Humans; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011175:Positive-Pressure Respiration; D012891:Sleep Apnea Syndromes; D013995:Time; D028761:Withholding Treatment", "nlm_unique_id": "101234523", "other_id": null, "pages": "363-6", "pmc": null, "pmid": "26312963", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "18489633;19275068;9501765;23100497;20509744;8997759;11122588;1798888;16547090;7944843", "title": "Sleep-disordered breathing in patients with opioid use disorders in long-term maintenance on buprenorphine-naloxone: A case series.", "title_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series" }

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SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015;11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088439, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00374RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL?11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160227", "receivedate": "20160227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12123852, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-2016-RO-00373RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SUMATRIPTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUMATRIPTAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, 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null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE AND NALOXONE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL;11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00373RO", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SUMATRIPTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUMATRIPTAN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "24 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL MAINTENANCE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "16 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HCL AND NALOXONE HCL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203326", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVIDO J,CONNERY H,HILL K. SLEEP-DISORDERED BREATHING IN PATIENTS WITH OPIOID USE DISORDERS IN LONG-TERM MAINTENANCE ON BUPRENORPHINE-NALOXONE: A CASE SERIES. JOURNAL OF OPIOID MANAGEMENT 2015 JUL?11:4:363-366.", "literaturereference_normalized": "sleep disordered breathing in patients with opioid use disorders in long term maintenance on buprenorphine naloxone a case series", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160227", "receivedate": "20160227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12123851, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Myocardial injury and acute coronary syndrome have been rarely associated with amoxicillin/clavulanic acid intake. The responsible pathogenetic mechanism is described by an amplified mast cell degranulation inducing coronary artery spasm and/or acute myocardial infarction in susceptible individuals which is called Kounis syndrome. We report here a case of Kounis syndrome presented with acute coronary syndrome due to amoxicillin/clavulanic acid use. All other etiologies, including ischemic reinfarction were appropriately ruled out.", "affiliations": null, "authors": "Tavil|Yusuf|Y|;Turfan|Murat|M|;Türkoğlu|Sedat|S|;Abaci|Adnan|A|", "chemical_list": "D019980:Amoxicillin-Potassium Clavulanate Combination", "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijcard.2006.11.165", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "124(1)", "journal": "International journal of cardiology", "keywords": null, "medline_ta": "Int J Cardiol", "mesh_terms": "D054058:Acute Coronary Syndrome; D019980:Amoxicillin-Potassium Clavulanate Combination; D000787:Angina Pectoris; D017023:Coronary Angiography; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D013577:Syndrome", "nlm_unique_id": "8200291", "other_id": null, "pages": "e4-7", "pmc": null, "pmid": "17360053", "pubdate": "2008-02-20", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Kounis syndrome secondary to amoxicillin/clavulanic acid use.", "title_normalized": "kounis syndrome secondary to amoxicillin clavulanic acid use" }

[ { "companynumb": "TR-RANBAXY-2013R1-73472", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "065109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OROPHARYNGEAL PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN + CLAVULANATE" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kounis syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAVIL Y, TURFAN M, TURKOGLU S, ABACI A. KOUNIS SYNDROME SECONDARY TO AMOXICILLIN/CLAVULANIC ACID USE. INT J CARDIOL. 2008;FEB 20;124(1):E4-7", "literaturereference_normalized": "kounis syndrome secondary to amoxicillin clavulanic acid use", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150305", "receivedate": "20150305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10890252, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Adverse reactions associated to anti-thyroid drugs include fever, rash, arthralgia, agranulocytosis and hepatitis that are thought to be hypersensitivity reactions. Five cases of pleural effusion associated to thionamides have also been reported, two with propylthiouracil and three with carbimazole.\n\n\n\nWe report here a case of a 75-year-old man admitted because of unilateral pleural effusion. The patient had a recent diagnosis of hyperthyroidism and 6 days after starting methimazole complained of pleuritic chest pain. He had elevated C-reactive protein and erythrocyte sedimentation rate and normal white blood cell count and liver enzymes. Chest radiography showed a moderate right pleural effusion and the ultrasound revealed a loculated effusion that was shown to be an eosinophilic exudate.\n\n\n\nThe temporal relationship between methimazole intake and the development of pleural effusion combined with the extensive exclusion of alternative causes, namely infectious, neoplastic and primary auto-immune diseases, led to the diagnosis of hypersensitivity reaction to methimazole. The thionamide was stopped and corticosteroid was started with complete resolution of the pleural effusion in 3 months. Awareness of this rare adverse reaction of anti-thyroid drugs is important and methimazole can be added to the list of possible etiologies of drug-induced eosinophilic pleural effusion.", "affiliations": "Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal. pgasparcosta@gmail.com.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Endocrinologia, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.;Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.", "authors": "Gaspar-da-Costa|Pedro|P|;Duarte Silva|Filipa|F|;Henriques|Júlia|J|;do Vale|Sónia|S|;Braz|Sandra|S|;Meneses Santos|João|J|;M M Victorino|Rui|R|", "chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole", "country": "England", "delete": false, "doi": "10.1186/s40360-017-0121-1", "fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 12110.1186/s40360-017-0121-1Case ReportMethimazole associated eosinophilic pleural effusion: a case report Gaspar-da-Costa Pedro pgasparcosta@gmail.com 1Duarte Silva Filipa filipacdds@gmail.com 1Henriques Júlia juliamhenriques@gmail.com 1do Vale Sónia soniavale@net.sapo.pt 23Braz Sandra sandrabbraz@gmail.com 13Meneses Santos João joaogms@hotmail.com 13M.M. Victorino Rui rui.victorino@chln.min-saude.pt 131 0000 0001 2295 9747grid.411265.5Serviço de Medicina 2, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035 Lisbon, Portugal 2 0000 0001 2295 9747grid.411265.5Serviço de Endocrinologia, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Prof. Egas Moniz, 1649-035 Lisbon, Portugal 3 0000 0001 2181 4263grid.9983.bFaculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal 21 3 2017 21 3 2017 2017 18 162 12 2016 28 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAdverse reactions associated to anti-thyroid drugs include fever, rash, arthralgia, agranulocytosis and hepatitis that are thought to be hypersensitivity reactions. Five cases of pleural effusion associated to thionamides have also been reported, two with propylthiouracil and three with carbimazole.\n\nCase presentation\nWe report here a case of a 75-year-old man admitted because of unilateral pleural effusion. The patient had a recent diagnosis of hyperthyroidism and 6 days after starting methimazole complained of pleuritic chest pain. He had elevated C-reactive protein and erythrocyte sedimentation rate and normal white blood cell count and liver enzymes. Chest radiography showed a moderate right pleural effusion and the ultrasound revealed a loculated effusion that was shown to be an eosinophilic exudate.\n\nConclusions\nThe temporal relationship between methimazole intake and the development of pleural effusion combined with the extensive exclusion of alternative causes, namely infectious, neoplastic and primary auto-immune diseases, led to the diagnosis of hypersensitivity reaction to methimazole. The thionamide was stopped and corticosteroid was started with complete resolution of the pleural effusion in 3 months.\n\nAwareness of this rare adverse reaction of anti-thyroid drugs is important and methimazole can be added to the list of possible etiologies of drug-induced eosinophilic pleural effusion.\n\nKeywords\nEosinophilic pleural effusionThionamidesMethimazoleHypersensitivity reactionCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nMethimazole or thiamazole, together with carbimazole and propylthiouracil, are anti-thyroid medications belonging to the class of thionamides [1]. Methimazole is the active metabolite of carbimazole and has similar pharmacological activity. Thionamides side effects are rare and include fever, rash, arthralgias, agranulocytosis and hepatitis [1]. Pleuro-pulmonary complications of these drugs are even rarer.\n\nThe mechanisms of thionamides side effects are poorly understood but are generally considered to be dose independent by immunologic hypersensitivity. Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis associated to anti-thyroid drugs have been well described [2–12]. Additionally, a drug-induced lupus-like syndrome and hypersensitivity reactions with cutaneous, renal or pulmonary involvement have also been identified [13–17]. Recently, five cases of pleural effusion induced by anti-thyroid drugs, two with propylthiouracil and three with carbimazole, have been reported in the literature [18–22].\n\nWe describe here a patient with hyperthyroidism who developed an unilateral eosinophilic pleural effusion a few days after the initiation of methimazole therapy. An extensive diagnostic evaluation excluded infectious and neoplastic diseases as well as primary auto-immune or vasculitic disease as the cause of serositis. Pleural effusion was thus considered as a manifestation of methimazole-hypersensitivity reaction. To the best of our knowledge, this is the first case of methimazole-induced pleural effusion described in the literature.\n\nCase presentation\nA 75-year-old man was admitted with unilateral right pleural effusion. He presented with pleuritic chest pain that started 4 days before and had no other relevant complaints, namely fever, diaphoresis, dyspnoea, cough, haemoptysis, rash or arthralgia.\n\nHe had a past medical history of arterial hypertension, atrial fibrillation, end-stage renal disease on haemodialysis, peripheral artery disease and prostatic hyperplasia. His ambulatory prescription consisted of enalapril, carvedilol, nifedipine, aspirin, warfarin, omeprazole and tansulosin, for more than 3 years. Amiodarone had been suspended, 2 months before, due to ocular toxicity. There was no evidence of thoracic trauma or previous asbestos exposure.\n\nTen days before hospital admission the patient had an episode of unstable angina. He underwent coronary angiography which showed a lesion in the circumflex artery and angioplasty and implantation of an intracoronary stent coated drug were performed. He started treatment with clopidogrel. By this time blood tests showed low TSH (0.055 uU/mL; reference range: 0.55–4.78 uU/mL) and high FT4 (1.81 ng/dL; reference range: 0.80–1.76 ng/dL) and FT3 (4.84 pg/mL; reference range: 2.3–4.2 pg/mL). Methimazole was started. There was no evidence of pleural effusion at that time.\n\nAt hospital admission the patient was afebrile, with a respiratory rate of 18 cycles per minute and oxygen saturation of 95% on room air. His blood pressure was 131/63 mmHg and heart rate was 76 beats per minute. Cardio-pulmonary examination revealed arrhythmic heart sounds, diminished breath sounds on the lower half of the right lung and dullness on percussion at that site was noted. All other findings on physical examination were unremarkable.\n\nLaboratory tests showed normal leucocytes (6 510/uL) and eosinophils (320/uL) counts, elevated C-reactive protein (10.9 mg/dL) and erythrocyte sedimentation rate (58 mm) and normal liver enzymes; TSH (0.019 uU/mL) was low and FT4 (2.51 ng/dL) and FT3 (7.22 pg/mL) were high; INR (1.13) was not in therapeutic range. Arterial blood gases, while the patient was in room air and after haemodialysis, showed hypoxemia (PO2: 57.6 mmHg) and metabolic alkalosis (pH: 7.48, PCO2: 37.8 mmHg, HCO3\n−: 28.9 mmol/L). Electrocardiogram revealed atrial fibrillation rhythm without acute ischaemic changes. Chest radiography showed a homogenous opacity in the lower half of the right pulmonary field and chest ultrasound findings were suggestive of pleural effusion with septa. Right-sided diagnostic thoracentesis was performed. The aspirated pleural fluid had 2277 cells/uL with 70% being macrophages, 18% eosinophils and 12% neutrophils. The effusion protein/serum protein ratio was 0.7 and the effusion lactate dehydrogenase (LDH)/serum LDH ratio was 1.8. Pleural fluid cultures revealed no bacteria or mycobacteria and no malignant cells were detected on cytological examination of pleural fluid. Bronchofibroscopy did not reveal any macroscopic lesion. Bronchoalveolar fluid cultures were negative and the cytological analysis of the fluid showed no malignant cells. Pleural biopsy was not performed due to high bleeding risk as the patient was on double anti-platelet and anticoagulation therapy. The blood cultures yielded no bacteria or mycobacteria and blood interferon gamma release assay for Mycobacterium tuberculosis was negative. Anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA) antibodies and ANCA were negative.\n\nThoracic, abdominal and pelvic computed tomography (CT) was performed and confirmed the moderate right pleural effusion with no other positive findings. Thoracic CT angiography excluded pulmonary embolism. Although Dressler syndrome was considered [23], it usually occurs after myocardial infarction rather than unstable angina and moreover, the short interval between the cardiac event and the pleural effusion did not support this hypothesis [24].\n\nTiters of thyroglobulin (Tg), anti-Tg, anti-thyroperoxidase and anti-TSH receptor antibodies were normal. The cervical ultrasonography revealed thyroid micronodules and there was no radioisotope uptake in the 99mTechnetium thyroid scintigraphy. Hyperthyroidism was interpreted as type II amiodarone induced thyrotoxicosis.\n\nAfter the exclusion of neoplastic, infectious and primary auto-immune diseases, considering an exudative pleural effusion with significant eosinophilia and a well-established temporal relation with the initiation of methimazole treatment, a diagnosis of methimazole-induced pleural effusion was made. A single organ drug hypersensitivity reaction was assumed in the absence of evidence of other organ involvement. Anti-thyroid medication was suspended, systemic corticosteroid was initiated and all other medications were maintained. Progressive and rapid clinical and laboratorial improvement was evident with normalization of inflammatory biomarkers and thyroid function and resolution of hypoxemia. Three months after methimazole was suspended there was complete resolution of pleural effusion.\n\nDiscussion\nThionamides-induced auto-immune phenomena, including pleuro-pulmonary complications, exhibit usually the features of ANCA-positive systemic vasculitis. Stankus et al. published, in 1992, the first case of propylthiouracil-induced hypersensitivity vasculitis and since then 61 cases of vasculitis associated to anti-thyroid drugs have been reported, most involving propylthiouracil [15, 25]. There are only nine reported cases of carbimazole-induced vasculitis and seven cases of vasculitis associated to methimazole [2–9, 13, 14, 17, 25–29]. In addition, a lupus-like syndrome can be induced by any of the thionamides [8, 13, 14, 21, 30]. Clinical manifestations are similar to systemic lupus erythematosus (SLE) and usually patients have positive anti-nuclear, anti-dsDNA and anti-histone antibodies [21].\n\nPleuro-pulmonary complications of thionamides are very rare and include alveolar hemorrhage, interstitial pneumonia, pulmonary cavitations and pleural effusion that are considered adverse auto-immune reactions triggered by these drugs [6, 7, 9, 18–22, 31, 32]. Five cases of anti-thyroid drug-induced pleural effusion, two with propylthiouracil and three with carbimazole, have been described in the literature [18–22]. The case reported here represents the first case of methimazole-associated pleural effusion. The temporal relationship between initiation of the drug and the appearance of pleural effusion, the resolution of the effusion after withdrawal of methimazole with administration of corticosteroid, in the absence of other potential cause for pleuritis, is consistent with the diagnosis of drug-induced pleural effusion. Our case differs from the previous reports by the short time between the initiation of the thionamide and the onset of pleural effusion that was only 6 days.\n\nPleural fluid of the two patients with propylthiouracil associated pleuritis was an eosinophilic exsudate, as in the case reported here [18, 19]. Pleural biopsy was made in one of these patients and showed chronic inflammation of the pleura with prominent eosinophils and both patients had negative auto-immune markers. None of the three patients with carbimazole-induced pleuritis had an eosinophilic exudate [20–22]. Two of these three reported cases had pleural nonspecific inflammatory infiltrates and negative auto-immunity, namely ANA and ANCA. The third patient had positive ANA, anti-dsDNA and anti-histone antibodies and pleuritis was considered as a drug-induced SLE-like syndrome.\n\nAs stated before, the mechanisms involved in these cases are most likely non-dose dependent, exactly like in drug induced liver injury where lesions occur via immunologic hypersensitivity [33] by generation of toxic metabolites [34] or alternatively metabolites that induce an immunological reaction [34, 35]. The inflammatory response with abundant eosinophils in the case reported here suggests that this represents a T cell drug hypersensitivity reaction with polarization to T helper 2 cells producing interleukin 4 and interleukin 5 that are known to induce eosinophil differentiation. Interestingly, a recent report by Uematsu et al. [36], identified a T helper 2 biased lymphocyte response in a model of methimazole acute liver injury mediated by microRNAs [36]. Another area of increasing interest is that of risk factors for methimazole adverse reactions. Thus, HLA-B*27:05 and other single nucleotide polymorphisms were identified as possible risk factors for anti-thyroid agranulocytosis [37], and the prospect that certain microRNAs with effects on lung development might represent prognostic tools in thyroid-dependent lung disease [38] has also been recently discussed.\n\nThe clinical and radiological evolution of this case was identical to the cases of pleural effusion induced by other thionamides. The anti-thyroid drug considered to be associated to the effusion was withdrawn in all patients and alternative anti-thyroid therapy options were initiated in three of the five patients [19, 20, 22]. The cessation of the drug was followed by resolution of the effusion within 3 to 5 months. Two of the five patients were given corticoesteroid for a short period of time and in decreasing dosages and in these cases a more rapid resolution of serositis was observed [19, 21]. In the present case, a diagnosis of type II hyperthyroidism, due to cytotoxic effect of amiodarone on thyroid cells, was made and thus maintenance of thionamides treatment was not required.\n\nConclusions\nIn conclusion, we describe here the first case of eosinophilic pleuritis associated to methimazole due to an hypersensitivity immune drug reaction with full remission after withdrawal the drug. Awareness of clinicians about the possibility of this drug adverse reaction may help identification of future similar cases.\n\nAbbreviations\nANAAnti-nuclear antibodies\n\nANCAAntineutrophil cytoplasmic antibody\n\nAnti-dsDNAAnti-double stranded DNA antibodies\n\nCTComputed tomography\n\nSLESystemic lupus erythematosus\n\nTgThyroglobulin\n\nAcknowledgements\nThe authors would like to thank the patient for granting consent for publication.\n\nFunding\nThis report received no research funding.\n\nAvailability of data and materials\nThe data that support the findings of this case are included in this published article.\n\nAuthors’ contributions\nPGC, JH, SV, SB and JMS analyzed and interpreted the present case and were involved in the diagnostic approach; PGC, FDS, JH, SV, SB, JMS and RMMV did a review of the literature; PGC, FDS and SB wrote a first draft. PGC, SB, SV, JMS and RMMV finalized the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor of this journal.\n\nEthics approval and consent to participate\nNot applicabale.\n==== Refs\nReferences\n1. Cooper DS Antithyroid drugs N Engl J Med 2005 352 905 17 10.1056/NEJMra042972 15745981 \n2. D’Cruz D Chesser AM Lightowler C Comer M Hurst MJ Baker LR Raine AE Antineutrophil cytoplasmic antibody-positive glomerulonephritis associated with anti-thyroid drug treatment Br J Rheumatol 1995 34 1090 1 10.1093/rheumatology/34.11.1090 8542214 \n3. Hori Y Arizono K Hara S Kawai R Hara M Yamada A Antineutrophil cytoplasmic antibodies-positive crescentic glomerulonephritis associated with thiamazole therapy Nephron 1996 74 734 5 10.1159/000189486 8956314 \n4. 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Hallberg P Eriksson N Ibañez L Bondon-Guitton E Kreutz R Carvajal A Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population Lancet Diabetes Endocrinol 2016 4 6 507 16 10.1016/S2213-8587(16)00113-3 27157822 \n38. Bjørnstad S Samara A Erichsen A Paulsen RE Glover JC Roald B Hampered lung maturation in methimazole-induced hypothyroidism in fetal chicken: morphological and molecular correlates to human fetal development Neonatology 2016 110 2 83 92 10.1159/000444656 27070722\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-6511", "issue": "18(1)", "journal": "BMC pharmacology & toxicology", "keywords": "Case report; Eosinophilic pleural effusion; Hypersensitivity reaction; Methimazole; Thionamides", "medline_ta": "BMC Pharmacol Toxicol", "mesh_terms": "D000368:Aged; D013956:Antithyroid Agents; D004804:Eosinophils; D006801:Humans; D008297:Male; D008713:Methimazole; D010996:Pleural Effusion", "nlm_unique_id": "101590449", "other_id": null, "pages": "16", "pmc": null, "pmid": "28320470", "pubdate": "2017-03-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9611379;6184983;27045053;19263707;27157822;7989705;6548111;8548997;19494377;1424898;16018796;10534640;10958312;26848607;15745981;8542214;9391255;19533803;8956314;11802538;22953074;27070722;6617272;23391946;8449103;9920055;2570272;1681385;11575291;17237613;12201217;15785249;12353714;12543903;10327480;6548829;10822221;27421576", "title": "Methimazole associated eosinophilic pleural effusion: a case report.", "title_normalized": "methimazole associated eosinophilic pleural effusion a case report" }

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METHIMAZOLE ASSOCIATED EOSINOPHILIC PLEURAL EFFUSION: A CASE REPORT. BMC PHARMACOLOGY AND TOXICOLOGY 2017;18(1):16.", "literaturereference_normalized": "methimazole associated eosinophilic pleural effusion a case report", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20170511", "receivedate": "20170428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13495247, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PT-B.I. 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angina unstable", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GASPAR-DA-COSTA P, DUARTE SILVA F, HENRIQUES J, DO VALE S, BRAZ S, MENESES S, ET AL.. METHIMAZOLE ASSOCIATED EOSINOPHILIC PLEURAL EFFUSION: A CASE REPORT. BMC PHARMACOLOGY AND TOXICOLOGY. 2017;18(16):.", "literaturereference_normalized": "methimazole associated eosinophilic pleural effusion a case report", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20171214", "receivedate": "20171109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14176187, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "PT-PFIZER INC-2017141817", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "018972", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, 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"drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ocular toxicity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GASPAR-DA-COSTA, P.. METHIMAZOLE ASSOCIATED EOSINOPHILIC PLEURAL EFFUSION: A CASE REPORT.. 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{ "abstract": "Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis.\n\n\n\nThirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured.\n\n\n\nADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study.\n\n\n\nClopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc.\n\n\n\nISRCTN63206606 . Registered 02/Dec/2014.", "affiliations": "Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece. kosdelis@gmail.com.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.;Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.", "authors": "Ntelis|Konstantinos|K|;Gkizas|Vasileios|V|;Filippopoulou|Alexandra|A|;Davlouros|Periclis|P|;Alexopoulos|Dimitrios|D|;Andonopoulos|Andrew P|AP|;Daoussis|Dimitrios|D|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D019010:Vascular Cell Adhesion Molecule-1; D012701:Serotonin; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine", "country": "England", "delete": false, "doi": "10.1186/s12891-016-1072-1", "fulltext": "\n==== Front\nBMC Musculoskelet DisordBMC Musculoskelet DisordBMC Musculoskeletal Disorders1471-2474BioMed Central London 107210.1186/s12891-016-1072-1Research ArticleClopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study Ntelis Konstantinos +30-2610-999 693+30-2610-993 982kosdelis@gmail.com Gkizas Vasileios Filippopoulou Alexandra Davlouros Periclis Alexopoulos Dimitrios Andonopoulos Andrew P. Daoussis Dimitrios Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece 17 5 2016 17 5 2016 2016 17 21311 12 2015 11 5 2016 © Ntelis et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nActivated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis.\n\nMethods\nThirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured.\n\nResults\nADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study.\n\nConclusion\nClopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc.\n\nClinical trial registration\nISRCTN63206606. Registered 02/Dec/2014.\n\nKeywords\nSystemic sclerosisSclerodermaClopidogrelDigital ulcersPlateletshttp://dx.doi.org/http://dx.doi.org/10.13039/501100003486Hellenic Rheumatology Society and Professional Organization for Rheumatologistsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSystemic Sclerosis (SSc) is a systemic rheumatic disease characterized by obliterative vasculopathy, autoimmunity and progressive fibrosis leading to tissue injury. The skin and several internal organs are involved during the disease course; involvement of vital organs leads to increased mortality and morbidity. To date, no approved disease-modifying therapies exist for the treatment of patients with SSc. Numerous experimental drugs or interventions have been investigated for the treatment of visceral fibrosis in systemic sclerosis, some of them demonstrating promising results [1–4]. However, the need for new therapeutic targets in SSc remains crucial.\n\nThe main pathogenetic model of SSc recognizes endothelial cell injury, immune activation and fibrosis as the key points in the disease process [5, 6]. Lately, accumulating evidence suggests that platelets are not just cell fragments regulating hemostasis, but may be active players in the pathogenesis of several inflammatory or autoimmune diseases, including SSc [7–9]. Evidence suggests that there may be increased platelet activity in patients with SSc, due to the underlying vascular damage [10, 11] and many platelet-derived molecules, such as beta-thromboglobulin, thromboxane B2 and platelet factor 4, have been reported to be elevated in patients with SSc [12, 13]. A recent study has provided evidence that serotonin (5-hydroxytryptamine [5-HT]) released in peripheral tissues upon activation of platelets may induce skin fibrosis through activation of fibroblasts via 5-HT2B receptors [14]. These data point to the direction of a novel pathogenetic model of SSc where platelets and serotonin act as the link between endothelial dysfunction and fibrosis (endothelial dysfunction → platelet activation → serotonin release → fibroblast activation → fibrosis). Moreover, inhibition of platelet activity by clopidogrel treatment leads to a reduction of fibrosis in bleomycin-induced and tight skin murine models of scleroderma [14]. It is not known whether serotonin levels are increased in patients with SSc, but it has been found to be elevated in closely related conditions, such as Raynaud’s phenomenon and pulmonary hypertension [15, 16]. Antiplatelet agents, such as aspirin, which have been used previously in patients with SSc in order to improve vasculopathy have failed to show any efficacy [17]. So far, the effect of platelets inhibition by clopidogrel, a P2Y12 receptor antagonist, has not been investigated in vivo in patients with SSc. Clopidogrel is indicated for adult patients suffering from myocardial infarction or acute coronary syndrome, ischemic stroke or established peripheral arterial disease. Clopidogrel inhibits adenosine diphosphate (ADP) binding to its platelet P2Y12 receptor and subsequently the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. ADP-dependent platelet activation is one of the pathways which lead to platelet activation.\n\nIn this study we aimed to assess whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can a) effectively suppress ADP-dependent activation of platelets, b) reduce circulating levels of serotonin, a significant profibrotic mediator and finally c) favorably affect fibrosis or vasculopathy in patients with systemic sclerosis. We report herein that clopidogrel effectively inhibits ADP-dependent activation of platelets but does not improve either fibrosis or endothelial function in patients with SSc. To the contrary, it may associate with a deterioration of disease course, triggering the development of new digital ulcers.\n\nMethods\nPatients\nWe enrolled 14 patients with a diagnosis of SSc, fulfilling the 2013 ACR/EULAR criteria for the classification of the disease [18]. One patient did not comply with treatment and was withdrawn from the study. Baseline demographic and clinical characteristics of the remaining 13 patients are presented in Table 1. Most patients were female (n = 12) with a mean age of 59.5 years and had limited disease (n = 8) with a mean disease duration of 10.9 years. All patients underwent a complete physical examination and a detailed review of their medical files prior to study enrolment. Other variables were also evaluated (full blood count, biochemistry profile, autoantibody profiles, electrocardiogram and cardiac ultrasound). All patients were Anti-Scl-70 (anti-topoisomerase I antibodies) or anti-ACA (anti-centromere antibodies) positive (n = 5 and n = 8 respectively) and had no change in medications administered during the last 6 months before enrollment. None of the study subjects was under any kind of antiplatelet treatment. No change in immunosuppressive treatment was allowed during the study. Exclusion criteria included a history of gastrointestinal or cerebral bleeding. ADP-dependent platelet activation was also measured in 28 patients with RA and 22 healthy subjects for control purposes. Most patients with RA were female (75 %) with a mean age of 59 years and a mean DAS28 of 2.9; no patient was receiving any antiplatelet agent. The majority of the patients with RA were on treatment only with synthetic DMARDs (71.4 %), mainly methotrexate, while the rest of them were receiving also a biologic DMARD (28.6 %). No patient was receiving drugs, such as antidepressants (including selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors and tricyclic anti-depressants), any kind of anti-psycotic agent, anti-migraine agents (triptans), anti-convulsants, anti-parkinsonian agents, opioids and tramadol, that interfere with levels of serotonin. Healthy subjects were mostly female (90.9 %) with a mean age of 55 years and were not on any kind of antiplatelet or other treatment. APA and DD formed the Safety Board of the study and were responsible for evaluating all adverse events.Table 1 Demographics, clinical characteristics and medications of study subjects\n\nPatient no/sex/age in years\tDisease Duration in years\tType of Disease\tOrgan Involvement\tConcurrent medications\t\n1/F/47\t5\tlimited\tGI\t-\t\n2/F/62\t12\tdiffuse\tLung,PAH,GI\tCYC\t\n3/M/55\t2\tlimited\tLung,GI\t-\t\n4/F/53\t12\tdiffuse\tLung,DU,GI\tMMF, Bos\t\n5/F/53\t12\tlimited\tLung,DU,GI\tPred, RTX, Bos\t\n6/F/78\t4\tdiffuse\tLung,DU,PAH,Musc\tPred, Bos, RTX\t\n7/F/57\t21\tlimited\tLung,DU,GI\tPred, Bos\t\n8/F/58\t3\tdiffuse\tLung,GI\tRTX\t\n9/F/66\t9\tlimited\tLung,GI\tMMF\t\n10/F/59\t17\tlimited\tMusc\t–\t\n11/F/65\t8\tlimited\tLung,GI\tRTX\t\n12/F/40\t22\tdiffuse\tLung,GI,Musc\tRTX\t\n13/F/81\t15\tlimited\tGI\t–\t\nPred: low dose prednisone; Bos: bosentan; MMF: mycophenolate mofetil; CYC: cyclophosphamide; RTX: rituximab\n\nDU: digital ulcers; Musc: musculoskeletal involvement; GI: gastrointestinal involvement; PAH: pulmonary arterial hypertension\n\n\n\nTreatment\nPatients with SSc were treated with the recommended dose of clopidogrel in everyday clinical practice (75 mg). Duration of the study had been planned to be 2 years. Finally, due to early discontinuation of the study, 12 patients completed 1 year of treatment, while one patient (#13) was treated with the study drug for 10 months.\n\nIndices of internal organ function\nStandard PFTs (pulmonary function tests) were performed every 6 months during the study, including assessment of forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLco) corrected for hemoglobin concentration. PFT parameters are expressed as a percentage of normal predicted values. Estimated glomerular filtration rate (eGFR) was calculated at baseline and at 1 year with the 4 variables MDRD (Modification of Diet in Renal Disease Study Group) formula [19]. Complete cardiac ultrasound study was performed at baseline and at 12 months and right ventricular systolic pressure (RVSP) was determined.\n\nOverall functional impairment\nAssessment of functional status was performed at baseline, 6 and 12 months using the modified for Scleroderma Health Assessment Questionnaire (SHAQ) [20].\n\nClinical assessment of skin thickening\nThe modified Rodnan skin score (MRSS) [21, 22] was used for clinical assessment of skin thickening at baseline and at 1 year, by two experienced assessors (DD and KN).\n\nLevels of circulating serotonin and s-VCAM1\nWhole blood was obtained from all participants at baseline and following 14 days of treatment. Platelet poor plasma was isolated from citrate tubes following a double centrifugation at 2000 g. Following the first centrifugation the top 75 % of plasma was removed with a plastic pipette, avoiding contamination, and underwent a second centrifugation at 2000 g. After the second centrifugation, the upper 75 % purified from the sedimented platelets, formed the platelet poor plasma. Samples from strenuous punctures were excluded. Serotonin was measured in these specimens with Radioimmunoassay (RIA) technique (DIAsource ImmunoAssays). Serum was also isolated at the same time points in order to evaluate the effect of treatment on the circulating levels of soluble vascular cell adhesion protein 1 (s-VCAM1), a marker of endothelial dysfunction [23]. Enzyme-linked immunosorbent assay (ELISA) technique was employed, using commercially available kit, according to the manufacturer’s instructions (R&D Systems, Minneapolis MN, USA). All samples were stored at -70 ° C.\n\nAssessment of ADP-dependent activation of platelets\nThe effect of treatment upon platelet activity was assessed through ADP-induced aggregation of platelets, measured by Multiplate Analyser (Roche), an instrument with five channels for parallel aggregometry measurements. Platelet activation was measured at baseline, following 14 days and 1 year of treatment. After 1:2 dilution of whole blood with 0.9 % NaCl solution and incubating for 3 min in the test cuvettes at 37 °C, the agonist (ADP) was added. Platelet aggregation was continuously recorded for 6 min. The adhesion and aggregation of platelets was measured by the change of electrical resistance between two sensor wires. Impedance is transformed to arbitrary aggregation units (AU) that are plotted against time (AU*min) [24]. Resistance to clopidogrel inhibition was defined as a AU*min value ≥468 on treatment [25].\n\nStatistical analysis\nStatistical analysis was performed using the GraphPad Prism software version 5. All variables were tested for normality using D'Agostino's test. Data are presented as mean ± SEM, median or percentages, as appropriate. The paired Student’s t-test and Wilcoxon matched pairs test, were used as indicated, for normal and non-normal distributions respectively. One-way ANOVA was used for group comparisons. Unpaired t-test was used to compare unpaired values. Correlations between ADP-dependent platelet activation and other variables were analyzed by Pearson or Spearman test, as appropriate. Values of p < 0.05 were considered as statistically significant.\n\nResults\nNo evidence of increased ADP-dependent platelet activation in patients with SSc\nWe first evaluated the ADP-dependent activation of platelets in patients with SSc compared to patients with RA and healthy subjects. No statistically significant differences were found between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). These data are diagrammatically depicted in Fig. 1a.Fig. 1 ADP-dependent platelet activation in patients with SSc is not increased compared to patients with RA and healthy subjects (a). Clopidogrel effectively inhibits ADP-dependent platelet activation in patients with SSc (b)\n\n\n\nSince many patients in our cohort had long standing disease we next sought to explore whether ADP-dependent platelet activation in patients with SSc correlates with disease duration. We found that ADP-dependent platelet activation in patients with early disease (as defined by disease duration ≤ 4 years, n = 3) was similar to that of patients with long standing disease (mean ± SEM AU*min: 315.7 ± 105.4 vs 415.0 ± 70.1 in patients with early vs late disease, respectively, p = 0.49). Moreover, no significant association of ADP-dependent platelet activation with age, gender, PFTs or MRSS in patients with SSc was found.\n\nThese data indicate that ADP-dependent platelet activation is not increased in patients with SSc, even in those with early disease despite the underlying vasculopathy; therefore, this particular pathway of platelet activation does not seem to be crucially involved in SSc pathogenesis.\n\nClopidogrel treatment effectively inhibits ADP-dependent activation of platelets in patients with SSc\nWe next assessed the effect of clopidogrel on ADP-dependent activation of platelets in patients with SSc. Following 14 days of clopidogrel treatment a significant reduction of ADP-depended activation of platelets was found in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, prior to and following treatment respectively, p = 0.014). These data are shown in Fig. 1b. This effect was sustained following one year of treatment (mean ± SEM AU*min: 157.2 ± 39, p = 0.005 compared to baseline). Two patients (15.4 %) showed resistance to clopidogrel inhibition and displayed high platelet reactivity (497 and 594 AU*min) despite treatment. These data show that clopidogrel is an effective inhibitor o ADP-dependent platelet activation in patients with SSc since the percentage of patients displaying resistance to clopidogrel inhibition (15.4 %) is even lower than that reported for the general population which is estimated to be up to 30 % [26, 27].\n\nClopidogrel treatment does not affect serotonin levels\nWe next assessed whether effective suppression of ADP-dependent platelet activation by clopidogrel can decrease circulating serotonin levels, a significant profibrotic mediator. Serotonin levels in platelet poor plasma did not change following 14 days of treatment with clopidogrel (mean ± SEM ng/dl: 178.3 ± 17.4 vs 210.6 ± 28.6, prior to and following treatment respectively, p = 0.17), despite the effective suppression of ADP-dependent activation of platelets at the same time point. Data are shown in Fig. 2a.Fig. 2 Effect of clopidogrel on serotonin and sVCAM1 levels. No change in serotonin levels in platelets poor plasma was found in patients with SSc following 14 days of treatment with clopidogrel (a). sVCAM1 levels are significantly increased following clopidogrel treatment in patients with SSc (b)\n\n\n\nClopidogrel treatment associates with worsening of endothelial function\nWe further evaluated the results of clopidogrel treatment on soluble VCAM1 levels as a marker of endothelial dysfunction/injury. There was a statistically significant increase of s-VCAM1 levels following 14 days of clopidogrel treatment (optical density mean ± SEM: 2.339 ± 0.211 vs 2.651 ± 0.139 before and following treatment respectively, p = 0.03) as shown in Fig. 2b. These data indicate that clopidogrel treatment does not improve but may actually worsen endothelial function in patients with SSc.\n\nClopidogrel treatment may associate with the development of new digital ulcers in patients with SSc\nThree patients, all with limited disease, developed new digital ulcers during the study; 2 of them did not have a history of digital ulcers. Patient #3 had early disease with a 3 year history of Raynaud’s phenomenon before the diagnosis, but no history of ulcers. Most striking, patient #13 had a longstanding disease of 15 years; she never had digital ulcers. Patient #4 had a 12 year history of disease but she has not developed any ulcers for the last 8 years, while on bosentan treatment. Patients #3, #4 and #13 developed the ulcers following 10, 9 and 10 months of treatment, respectively. In patients #13 and #3 we initiated treatment with bosentan with a good response after a short period, while patient #4 was treated with iloprost and antibiotics showing also a rapid improvement. None of the patients had any changes in everyday lifestyle during the study including exposure to cold. Following the development of digital ulcers in patient #13 the Safety Board of the study decided to withdraw all patients from the study medication, concluding that there may be an association between treatment and development of new ulcers. At that time point all patients, apart from patient #13, had completed 1 year on treatment. No other serious adverse events were recorded during the study. The main side effects included a transient rash after treatment initiation in patient #7 and minor bruising episodes in patients #5 and #9.\n\nEffect of Clopidogrel treatment on clinical outcomes\nTo evaluate any potential clinical effect of clopidogrel treatment we performed a complete physical exam, evaluation of skin thickening, evaluation of pulmonary function, basic laboratory work up and finally evaluation of general functional status. Clopidogrel treatment had no significant effect on skin thickening (mean ± SEM 10.69 ± 0.62 vs 9.85 ± 0.84 at baseline vs 1 year, respectively, p = 0.12). We did not detect any statistically significant differences in all indices of internal organ function we examined. FVC remained stable following 1 year of treatment (mean ± SEM 93.75 ± 5.58 vs 92.67 ± 5.04 at baseline vs 1 year, respectively, p = 0.69), the same was found for DLco (mean ± SEM 65.08 ± 4.31 vs 62.67 ± 4.85 at baseline vs 1 year respectively, p = 0.39). SHAQ also showed no significant change following one year of treatment with clopidogrel (mean ± SEM: 0.80 ± 0.11 vs 0.98 ± 0.14, p = 0.16). RVSP and EGFR also remained stable following 1 year of treatment. Data are diagrammatically shown in Fig. 3.Fig. 3 Effects of clopidogrel on clinical outcomes. Clopidogrel treatment does not have any significant impact on clinical outcomes (MRSS (a), FVC (b), DLco (c) and EGFR (d)) in patients with SSc\n\n\n\nDiscussion\nWe report herein the results of an open label, proof of principle study evaluating the efficacy of clopidogrel in patients with SSc. So far, ADP-dependent platelet activation has not been investigated in SSc with newer techniques. The potential role of platelets in the pathogenesis of SSc has been explored in SSc but data are still controversial. Several studies demonstrate increased platelet activation using different agents as agonists [28, 29], but this was not a consisted finding [30].\n\nIn our study we found no evidence of increased ADP-dependent platelet activation in patients with SSc, even in those with early disease, compared to patients with RA and healthy subjects, indicating that this particular pathway of platelet activation may not be crucially involved in SSc pathogenesis. However, one should take into account that SSc is an extremely heterogeneous disease and therefore, definite conclusions cannot be drawn based on data derived from a small number of patients. One cannot exclude the possibility that there may be a subset of patients with SSc displaying increased ADP dependent platelet activation; we cannot rule out that in these particular patients clopidogrel might have some efficacy.\n\nMoreover, we demonstrated that clopidogrel can effectively inhibit the ADP-dependent activation of platelets in the majority of SSc patients. Previous studies have reported that resistance to clopidogrel inhibition in particular populations, such as patients with chronic kidney failure under hemodialysis, can reach up to 84 % [31]. In our study only two of 13 SSc patients showed resistance to clopidogrel; this percentage (15.4 %) is even lower than that reported for the general population, which is estimated to be up to 30 % [26, 27].\n\nBased on experimental data which indicate that platelets may be involved in the fibrotic process, we aimed at exploring whether platelet inhibition by clopidogrel could favorably affect fibrosis in patients with SSc, offering thus an adjunct therapeutic approach for the disease. There is evidence that serotonin is an important mediator in SSc which links vascular damage, platelets and fibrosis. Serotonin, a molecule stored in platelets, has been shown to possess profibrotic properties [32, 33]. However, there is no robust evidence that plasma free serotonin is increased in SSc. Biondi et al reported such a finding in patients with secondary Raynaud’s phenomenon [15], but Klimiuk et al found no evidence of this increase in patients with SSc [34]. In our study, effective inhibition of ADP dependent platelet activation with clopidogrel did not affect serotonin levels.\n\nFinally, our data suggest that clopidogrel may associate with worsening of endothelial function and development of new digital ulcers in patients with SSc. Although platelets are considered to promote vasoconstriction, it is also known that they produce nitric oxide (NO) as well [35]. NO is a vasodilator which mainly derives from endothelial cells and consists an important modulator of vascular tone. It has been found that NO production from platelets is increased in chronic kidney failure [36], another condition characterized by generalized vasculopathy, and may have a protective role against cardiovascular risk. In addition, there are also studies demonstrating some protective features of platelets regarding fibrosis and vascular function. In two murine models of liver damage platelets seem to prevent fibrosis [37] and promote liver tissue repair [38]. Joshi et al showed that platelet depletion delays resolution of necrosis in the postischemic liver, suggesting that the presence of platelet-derived factors is necessary for tissue remodeling [37].\n\nMoreover, Holowatz et al reported that platelet inhibition with clopidogrel attenuated reflex vasodilation, in middle aged women, suggesting platelet involvement in reflex vasodilation through the release of vasodilating factors. Investigators found that clopidogrel decreased skin blood flow responses during hyperthermia [39]. This effect may be of importance in SSc patients and may explain the development of new digital ulcers in our study. All the above data suggest that platelets under certain conditions may have properties which improve endothelial function and enhance vasodilation and tissue repair, rather than provoke tissue injury.\n\nConclusions\nOverall, our data indicate that clopidogrel may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis. This study in combination with previous reports of failure of antiplatelet agents in SSc, indicates that platelets may not play a crucial role in SSc pathophysiology, at least in late stages. Moreover, our data indicate that clopidogrel should be used cautiously in patients with SSc. This becomes even more important nowadays, as it is becoming clear that patients with SSc have increased cardiovascular morbidity and frequently need antiplatelet treatment [40]. Aspirin may be a more suitable therapeutic option for these patients. Our findings originate from a small uncontrolled trial and further investigation with larger cohorts is warranted.\n\nEthics approval and consent to participate\nA local (Patras University Hospital, Patras, Greece) Ethics Committee approved the study protocol (which fulfilled the Declaration of Helsinki requirements) and written informed consent was obtained from all participants.\n\nConsent for publication\nNot applicable.\n\nAvailability of data and materials\nExperimental data are available in LabArchives repository https://mynotebook.labarchives.com/share_attachment/kostas/MTkuNXwxNzk0NjAvMTUtMi9UcmVlTm9kZS8zODM0NTIxMjM4fDQ5LjU=xMjM4fDQ5LjU=\n\nAbbreviations\nSScSystemic Sclerosis\n\n5-HT5-hydroxytryptamine\n\nRArheumatoid arthritis\n\nADPadenosine diphosphate\n\nAnti-Scl-70anti-topoisomerase I antibodies\n\nanti-ACAanti-centromere antibodies\n\nPFTspulmonary function tests\n\nFVCforced vital capacity\n\nDLcodiffusing capacity of carbon monoxide\n\nRVSPventricular systolic pressure\n\neGFRestimated glomerular filtration rate\n\nMDRDmodification of diet in renal disease study group formula\n\nSHAQscleroderma health assessment questionnaire\n\nMRSSmodified Rodnan skin score\n\nRIAradioimmunoassay\n\ns-VCAM1soluble vascular cell adhesion protein 1\n\nELISAenzyme-linked immunosorbent assay\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nDA, APA and DD participated in the conception and design of the study. DA and APA revised the manuscript. KN and DD performed the literature search, the statistical analysis and wrote the manuscript. KN, AF and VG performed the experimental part of the study. PD helped to interpret the data. All authors read and approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis work was supported by the Hellenic Rheumatology Society and Professional Organization for Rheumatologists (a non-profitable organization which did not interfere in any stage of this study)\n==== Refs\nReferences\n1. Daoussis D Liossis S-NC Tsamandas AC Kalogeropoulou C Kazantzi A Sirinian C Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study Rheumatology (Oxford) 2010 49 2 271 80 10.1093/rheumatology/kep093 19447770 \n2. Naraghi K van Laar JM Update on stem cell transplantation for systemic sclerosis: recent trial results Curr Rheumatol Rep 2013 15 5 326 10.1007/s11926-013-0326-2 23516015 \n3. 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Chu S-Y Chen Y-J Liu C-J Tseng W-C Lin M-W Hwang C-Y Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study Am J Med 2013 126 11 982 8 10.1016/j.amjmed.2013.06.025 24157289\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2474", "issue": "17()", "journal": "BMC musculoskeletal disorders", "keywords": "Clopidogrel; Digital ulcers; Platelets; Scleroderma; Systemic sclerosis", "medline_ta": "BMC Musculoskelet Disord", "mesh_terms": "D000244:Adenosine Diphosphate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000077144:Clopidogrel; D004730:Endothelium, Vascular; D005260:Female; D005385:Fingers; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors; D000075082:Proof of Concept Study; D058921:Purinergic P2Y Receptor Antagonists; D012595:Scleroderma, Systemic; D012701:Serotonin; D012883:Skin Ulcer; D013988:Ticlopidine; D019010:Vascular Cell Adhesion Molecule-1", "nlm_unique_id": "100968565", "other_id": null, "pages": "213", "pmc": null, "pmid": "27188755", "pubdate": "2016-05-17", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "12922968;12796140;6386002;3397197;2774700;1888199;2151867;1839040;1382417;7562759;8712862;9146760;10075613;15818719;15837243;17256748;17901370;17917538;19264241;19167402;19132559;19521548;19447770;20360429;20564397;20828644;20004954;21090968;21518801;21985070;22244622;22868927;23516015;24092682;24157289;25353084;11031209;12465153;12634924;6229551", "title": "Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study.", "title_normalized": "clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis results from an open label proof of concept study" }

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{ "abstract": "A 58-year-old woman presented with a 3-week history of a pruritic rash, which had started a week after commencing treatment with amlodipine. On physical examination, large, well-demarcated erythematous plaques, surrounded by small clusters of clear vesicles, were seen on the patient's torso. Subepidermal blisters with neutrophils and eosinophils were seen in a skin biopsy, and direct immunofluorescence showed deposition of IgA along the basement membrane, in keeping with a diagnosis of linear IgA dermatosis (LAD). Amlodipine was discontinued, and the patient was started on prednisolone 30 mg, supplemented shortly afterwards by dapsone, which resulted in prompt resolution of the rash. Only a few cases of drug-induced LAD have been reported, mostly in association with vancomycin. To our knowledge, this is the first reported case precipitated by amlodipine.", "affiliations": "Department of Dermatology, Mint Wing A, St Mary's Hospital, London, UK. lynette_low@hotmail.com", "authors": "Low|L|L|;Zaheri|S|S|;Wakelin|S|S|", "chemical_list": "D002121:Calcium Channel Blockers; D007070:Immunoglobulin A; D017311:Amlodipine", "country": "England", "delete": false, "doi": "10.1111/j.1365-2230.2011.04297.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0307-6938", "issue": "37(6)", "journal": "Clinical and experimental dermatology", "keywords": null, "medline_ta": "Clin Exp Dermatol", "mesh_terms": "D017311:Amlodipine; D002121:Calcium Channel Blockers; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007070:Immunoglobulin A; D008875:Middle Aged; D012871:Skin Diseases", "nlm_unique_id": "7606847", "other_id": null, "pages": "649-51", "pmc": null, "pmid": "22299719", "pubdate": "2012-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Amlodipine-induced linear IgA disease.", "title_normalized": "amlodipine induced linear iga disease" }

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{ "abstract": "Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.", "affiliations": "Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; and.;Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; and.;Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands.;Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.", "authors": "Berger|Gerbrig|G|;Kroeze|Leonie I|LI|;Koorenhof-Scheele|Theresia N|TN|;de Graaf|Aniek O|AO|;Yoshida|Kenichi|K|;Ueno|Hiroo|H|;Shiraishi|Yuichi|Y|;Miyano|Satoru|S|;van den Berg|Eva|E|;Schepers|Hein|H|;van der Reijden|Bert A|BA|;Ogawa|Seishi|S|;Vellenga|Edo|E|;Jansen|Joop H|JH|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1182/blood-2017-09-805879", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "131(16)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000328:Adult; D000368:Aged; D064592:Autografts; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D009196:Myeloproliferative Disorders; D016609:Neoplasms, Second Primary; D012189:Retrospective Studies", "nlm_unique_id": "7603509", "other_id": null, "pages": "1846-1857", "pmc": null, "pmid": "29311096", "pubdate": "2018-04-19", "publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT.", "title_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct" }

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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190130", "receivedate": "20190130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15889734, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019057181", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (AS A PART OF BEAM REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (AS A PART OF BEAM REGIMEN)", "drugenddate": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROCARBAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (AS A PART OF R-LPP REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROCARBAZINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (AS A PART OF R-LPP REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (AS A PART OF R-LPP REGIMEN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm progression", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER, G.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190214", "receivedate": "20190214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15963914, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003860", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850414, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003896", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF RFC REGIMEN; 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848774, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019055471", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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"reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848767, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019072446", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROPOIETIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, 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"62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mean cell volume increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190228", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15986197, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-LANNETT COMPANY, INC.-NL-2019LAN000140", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931858, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-005982", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, 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"24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Berger G, Kroeze LI, Koorenhof-Scheele TN, de Graaf AO, Yoshida K et al.. Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT.. Blood. 2018;131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20220104", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17114158, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "NL-MYLANLABS-2019M1003901", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT. Blood. 2018;131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20211231", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17114578, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000042", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15932066, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019070617", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, EDO. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15981666, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000032", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131:16:1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190228", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15986126, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000039", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood stem cell transplant failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL... EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200131", "receivedate": "20200131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17356019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NL-PFIZER INC-2019055626", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF LOPP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, 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"PROCARBAZINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF LOPP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15951269, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003892", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131 (16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15934529, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000033", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transformation to acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931749, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003873", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848789, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003872", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848852, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003887", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-ROCHE-2264041", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", 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"UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-57.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200622", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15975872, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000034", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOTHERAPY" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931822, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019070413", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER, G.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131 (16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190220", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15976352, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003876", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848770, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019070587", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLEGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15985960, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-PFIZER INC-2019070508", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "072168", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190225", "receivedate": "20190219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15981660, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003866", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH-DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850420, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003853", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, 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"reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190118", "receivedate": "20190118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15844670, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003868", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848790, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-TEVA-2019-NL-1004150", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190131", "receivedate": "20190131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15896595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003899", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15848905, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019057192", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (HIGH DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "209191", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, EDO. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. 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EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. 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"5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190130", "receivedate": "20190130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15889731, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2020M1011892", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "200914", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-57", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200204", "receivedate": "20200204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17367321, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "NL-MYLANLABS-2019M1003858", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850411, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019072516", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VELLENGA, E.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD. 2018?131:16:1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "NL", "receiptdate": "20190228", "receivedate": "20190220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15984451, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NL-MYLANLABS-2019M1003888", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, 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"patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mean cell volume increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15850441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-MYLANLABS-2019M1003856", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090270", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMUSTINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF BEAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT. BLOOD 2018?131(16):1846-1857.", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190118", "receivedate": "20190118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15844683, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2019COR000038", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RADIATION THERAPY" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOTHERAPY" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARMUSTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BERGER G, KROEZE LI, KOORENHOF-SCHEELE TN, DE GRAAF AO, YOSHIDA K, UENO H, ET AL.. EARLY DETECTION AND EVOLUTION OF PRELEUKEMIC CLONES IN THERAPY-RELATED MYELOID NEOPLASMS FOLLOWING AUTOLOGOUS SCT.. BLOOD. 2018?131(16):1846-1857", "literaturereference_normalized": "early detection and evolution of preleukemic clones in therapy related myeloid neoplasms following autologous sct", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190207", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15931933, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "NL-PFIZER INC-2019045307", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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{ "abstract": "Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA). We present a case of acute chest pain in a 58-year-old male with severe asthma, which regressed after sublingual administration of nitroglycerine. At the time of hospital admission, there were non-specific ST-changes on the ecg, coronary enzymes were increased, and the patient was concluded to have a non-ST-elevation myocardial infarction, and treated as such. A subacute cardiac catheterization showed no signs of significant coronary stenosis. During the next days, there was increasing pain and reduced strength in both feet. Paraclinical imaging and neurological examinations could not explain the symptoms, and physiotherapy was initiated. At the time, no connection to patient's diagnosis of severe asthma was made. The patient was seen in the respiratory outpatient clinic for a routine check-up, three weeks after the initial hospital admission. At this point, there was increasing pain in both legs and the patient had difficulty walking and experienced increasing dyspnea. Blood eosinophils were elevated (12.7 × 10(9)/L), and an acute HRCT scan showed bilateral peribronchial infiltrates with ground glass opacification and small noduli. A diagnosis of EGPA was established, and administration of systemic glucocorticoids was initiated. A year and a half later, there is still reduced strength and sensory loss. This case illustrates that it is important to consider alternative diagnoses in patients with atypical symptoms and a low risk profile. Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), which makes a quick diagnosis and prompt initiation of correct treatment imperative.", "affiliations": "Department of Lung medicine, Bispebjerg University Hospital, Denmark.;Department of Lung medicine, Bispebjerg University Hospital, Denmark.", "authors": "Bang|Cæcilie Larsen|CL|;Porsbjerg|Celeste Michala|CM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2016.08.004", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30077-610.1016/j.rmcr.2016.08.004Case ReportThink twice – Diagnostic delay in a patient with acute chest pain Bang Cæcilie Larsen bang.caecilie@gmail.com∗Porsbjerg Celeste Michala Department of Lung medicine, Bispebjerg University Hospital, Denmark∗ Corresponding author. bang.caecilie@gmail.com20 8 2016 2016 20 8 2016 19 94 97 1 5 2016 12 8 2016 15 8 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Heart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA).\n\nWe present a case of acute chest pain in a 58-year-old male with severe asthma, which regressed after sublingual administration of nitroglycerine. At the time of hospital admission, there were non-specific ST-changes on the ecg, coronary enzymes were increased, and the patient was concluded to have a non-ST-elevation myocardial infarction, and treated as such.\n\nA subacute cardiac catheterization showed no signs of significant coronary stenosis. During the next days, there was increasing pain and reduced strength in both feet. Paraclinical imaging and neurological examinations could not explain the symptoms, and physiotherapy was initiated. At the time, no connection to patient's diagnosis of severe asthma was made.\n\nThe patient was seen in the respiratory outpatient clinic for a routine check-up, three weeks after the initial hospital admission. At this point, there was increasing pain in both legs and the patient had difficulty walking and experienced increasing dyspnea. Blood eosinophils were elevated (12.7 × 109/L), and an acute HRCT scan showed bilateral peribronchial infiltrates with ground glass opacification and small noduli.\n\nA diagnosis of EGPA was established, and administration of systemic glucocorticoids was initiated. A year and a half later, there is still reduced strength and sensory loss.\n\nThis case illustrates that it is important to consider alternative diagnoses in patients with atypical symptoms and a low risk profile.\n\nHeart involvement is the most critical and potentially lethal systemic manifestation in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), which makes a quick diagnosis and prompt initiation of correct treatment imperative.\n\nKeywords\nAsthmaAcute chest painEosinophilic granulomatosis with polyangiitisEGPA\n==== Body\n1 Introduction\nEGPA is a vasculitis of the small and medium size arteries. EGPA is associated with severe asthma and eosinophilia in blood and tissue [1]. The diagnostic criteria accordingly to the American College of Rheumatology (ACR), is the presence of four or more of these six:\n\n1) Asthma, 2) Greater than ten percent eosinophils on the differential leucocyte count, 3) Mononeuropathy (including multiplex) or polyneuropathy, 4) Migratory or transient pulmonary opacities detected radiographically, 5) paranasal sinus abnormality, 6) Biopsy containing a vessel showing accumulation of eosinophils in extravascular areas [2].\n\nThere are great variations in the clinical presentation of EGPA, with cardiac involvement within about one third of the patients [3] and the clinical presentation also varies according to ANCA status with higher frequency of cardial involvement in patients with ANCA negative status [4].\n\nHere, we will discuss the importance of considering a diagnosis of EGPA in patient with previously known asthma who develops chest pain. Specifically, the presence of symptoms from more than one organ system should lead the thought to a systemic disease such as EGPA, being rare but serious.\n\n2 Case presentation\nSudden chest pain developed in a 56-year old male, ex-smoker with 15 pack years, normal BMI, and very physically active, performing triathlon and cycling 40 km per day.\n\nThere was no previous history of heart disease, but two years earlier the patient was diagnosed with asthma, with symptoms related to exercise.\n\nThe asthma was highly unstable and difficult to treat, with over 6 asthma exacerbations per year, requiring frequent courses of oral prednisone. The anti-asthmatic treatment included high-dose inhaled corticosteroids, long-acting beta-2-agonist, long-acting anticholinergic, theophylline and montelukast.\n\nDespite a daily dose of 15 mg prednisone daily for a period, the patient continued to have many exacerbations. The exacerbations receded after omalizumab was commenced. Prior to the admission there was no worsening of the asthma symptoms.\n\nThe chest pain lasted for hours, and the patient described a difficulty of reaching his standard max pulse during exercise the days before. At admission, the respiration frequency was 13, heart rate 60, blood pressure 110/70 and the saturation was 97% without oxygen supplement. Auscultation examination was normal.\n\nThe electrocardiogram (ECG) showed sinus rhythm, heart rate of 55 and no significant signs of infarction, but there was hammock-like ST changes in the antero-lateral leads. There was a cardial troponin I elevation up to 25800 ng/L and creatine kinase MB elevation up to 96.7 μg/L, and an eosinophil count of 3.57 × 109/L, C-Reactive protein (CRP) 8.\n\nEchocardiography (ECCO) showed normal ejection fraction and a computed axial tomography scan (CT) scan of the heart was also normal.\n\nIt was suspected that the patient had a non ST-elevation myocardial infarction, and after administration of sublingual nitroglycerin, the pain regressed. Cardiac catheterization showed a non-significant stenosis, too small for intervention.\n\nThe subsequent day, the patient developed pain in the right groin, at the site where he had been catheterized. A hematoma with a diameter of 5 × 10 cm was found on ultrasound, and interpreted to be the cause of the pain. Later, in addition to the pain, the patient described decreased sensibility and strength of the right foot.\n\nUltrasound of the right groin showed edema, no sign of pseudo aneurism, and again, normal echocardiography.\n\nOn day five, the patient experienced that the left foot suddenly gave way under him. A neurologic exam showed decreased sensibility laterally on the left leg, and he was unable to walk on toes and heels. Because of the pain and decreased sensibility and strength, a CT of the abdomen and a Magnetic resonance scan (MRI) of the columna was performed. The CT scan showed no sign of retroperitoneal bleeding and the MRI scan showed slight protrusion of the discus on level L4/L5, otherwise normal. Electromyography was normal, and the assessment by the neurologist was that the symptoms was of non-organic origin (functional).\n\nThe patient was then referred for physiotherapy and he was released from the hospital on aspirin, brilique and simvastatin.\n\nOn day twenty-two, the patient came for a planned routine check-up at the outpatient clinic at the department of respiratory medicine. At this point, bilateral loss of strength was pronounced and he was mobilized on crutches, and experienced progressive sensory loss and dysesthesia in both legs, now with a stocking distribution.\n\nWhen examined, he was found to be short of breath, the temperature was 38.4° Celsius, and there was right sided peroneal paresis.\n\nHis eosinophil count was 12.7 × 109/L, antineutrophil cytoplasmatic antibodies (ANCA) was negative, the total white blood cell count was 18.8 × 109/L and CRP 48 mg/L.\n\nAn acute high resolution CT scan (HRCT, Fig. 1) of the lungs was performed, and showed peribronchial consolidated infiltrates and areas with subpleural ground glass attenuation in the right lower lobe (1d). Bilaterally there were small nodules. Compared to the previous CT scan of the heart, there was now an increased size of the heart, and pericardial effusion. ECCO showed thickening of the myocardium, pericardial effusion (5mm), and estimated ejection fraction of 40%. There was a slightly increase of troponin and creatin kinase MB. There was no sign of arrhythmia.\n\nThe patient was admitted to a tertiary lung and cardiology department, on suspicion of pericarditis or endocarditis, and immunosuppressive therapy was started immediately (see below).\n\nThe diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss) was made on the basis of the combination of cardial involvement, lung affection, and the presence of polyneuropathy, and highly elevated eosinophils, on a background of severe asthma.\n\n3 Differential diagnosis\nAt the initial admission, the chest pain which regressed after administration of nitroglycerine, and the coronary enzyme elevation, as well as the small stenosis on heart catheterization could be explained as NSTEMI. However, the stenosis was insignificant, the CT of the heart was normal and the patient developed neurological symptoms shortly after admission. The hematoma in the hours after heart catheterization could initially explain the dysesthesia, but the increase and the loss of strength in addition, and the dissemination to the left foot as well, were not likely to be caused by the hematoma. The insignificant protrusion of discs seen on the MRI could not explain the neurological symptoms, and especially combined with the cardial involvement. Since no biopsy could verify vasculitis, and no paraclinical examination could explain the symptoms, it was considered that they could be of non-organic origin. A contact to the asthma specialist who followed the patient or a MRI scan of the heart might have given the diagnosis earlier.\n\nThe frequent treatment with prednisone could have masked eventual previous neurological symptoms and maybe even chest pain.\n\nThe treatment with omalizumab could have caused the angina and the later thrombosis, as this is reported as side effects [5]. But it seems unlikely that omalizumab alone could have caused both the pericardial effusion, the high eosinophil count, and the neurological symptoms.\n\n4 Treatment\nHigh dose methylprednisone was initiated in a dose of 1 g three times a day for the first three days. On day two, 800 mg of cyclophosphamide was added. After the first three days, the prednisone dose was run down to 50 mg per day and further reduced over the next days. The treatment with immunosuppressant was maintained with orally methotrexate once a week for three months, this was then converted to intravenously administered cyclophosphamide once a month, because of persisting peroneal paresis and development of a deep venous thrombosis.\n\n5 Outcome and follow-up\nAt the end of the high dose methylprednisone, the eosinophil count had normalized and the dysesthesia had regressed. Likewise, the dyspnea disappeared. Within a few days, the TnI level normalized, EF normalized within weeks and the pericardial effusion regressed.\n\nThe following weeks, the paresis of the feet improved, but the paresis persisted in the right peroneal nerve. A year and a half later there is still peroneal paresis, but no sign of relapse of EGPA.\n\n6 Discussion\nThe patient presented here has both asthma, hypereosinophilia, polyneuropathy and migratory infiltrates in both lungs, and thereby meets four out of the six diagnostic criteria listed by the ACR (see “Introduction”). EGPA is a rare vasculitis, and develops especially among patients with asthma and eosinophilia [6]. This vasculitis has both pulmonary and extra pulmonary involvement, and there exists a great span in the clinical presentation with symptoms from the lungs and upper airways (asthma), skin, the cardiovascular system, the peripheral nervous system, the kidneys, the gastrointestinal tract and the musculoskeletal system [4], [6].\n\nCardial involvement in EGPA is serious and frequent. The most frequent described findings are pericardial effusion and clinical signs of heart failure [3]. ECG changes with ST abnormalities and arrhythmias, MRI with sign of endocarditis and cardiomyopathy, and signs of valve dysfunction and elevated troponins is also described [3]. In the referenced study, all patients with cardial involvement previously had no cardial symptoms. EGPA was associated with high eosinophil count at the time of diagnosis, as was the case presented here.\n\nCardial symptoms as the presenting symptom of EGPA are described in similar cases [7], [8], [9], with manifestations such as pericardial effusion [7], [8], [9] elevated troponins [8] and reduced left ventricular function and ECG changes with new Q-waves [9].\n\nOnly one case was similar to ours, regarding presenting symptoms of angina, with no severe risk factors of heart disease, on a background of late-onset asthma, and with concomitant development of polyneuropathy during admission. However, fever and transient visual disturbances was described prior to admission [10].\n\nOnly a minority of EGPA patients are positive for ANCA (14 and 28% [3], [4]). Two studies have suggested that ANCA status among EGPA patients is associated with different organ involvement. ANCA negative status was associated with cardial involvement, as it was the case with the patient presented here. ANCA positive status was more frequent among patients with involvement of the peripheral nerve system, kidney and symptoms from ear, nose and throat [4], [6].\n\nThe prognosis of EGPA can be assessed with the five factor score system (FFS), where the presence of each of the following is given 1 point: 1) Cardiac involvement 2) Gastrointestinal involvement 3) Renal insufficiency 4) Proteinuria 5) Central Nervous system involvement [6]. Patients with a FSS from 0 usually achieves remission on systemic glucocorticoid treatment, and when the symptoms are under control, a reduction is recommended. With a FFS ≥1 the typical treatment is a combination of systemic glucocorticoids and cyclophosphamide, either once a month or daily. The duration remains controversial. The patient presented was given a combination of systemic glucocorticoids and cyclophosphamide.\n\nThe subgroup of EGPA patients with negative ANCA status and with cardiomyopathy had the poorest prognosis [4] and the prognosis was also worst for patients with endocarditis [3]. This emphasizes the importance of avoiding delay in the diagnostic process and initiation of treatment.\n\n7 Conclusion\nIn conclusion, this case emphasizes the importance of considering other causes of chest pain in a patient with a low risk profile and an atypical presentation. In particular, the development of neurological symptoms simultaneously with cardial symptoms on a background of severe asthma should prompt a suspicion of EGPA.• Chest pain and TnI elevations in a patient without risk factors for ischemic heart disease should lead to considerations regarding alternative diagnoses.\n\n• In a patient with late-onset eosinophilic asthma, development of extrapulmonary organ manifestations, including symptoms of vasculitis and neuritis, should lead to a suspicion of EGPA.\n\n• Fast and correct diagnosis and initiation of treatment is important to prevent permanent injury, and may prevent lethal outcomes\n\n\n\nFig. 1 High Resolution Computed axial Tomography scan showed peribronchial consolidated infiltrates bilaterally as well as small nodules (1a–c) and areas with subpleural ground glass attenuation in the right lower lobe (1d). Compared to the previous CT scan of the heart, there was now an increased size of the heart, and pericardial effusion.\n\nFig. 1\n==== Refs\nReferences\n1 Groh M. Pagnoux C. Baldini C. Bel E. Bottero P. Cottin V. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management Eur. J. Intern Med. 26 2015 545 553 25971154 \n2 Masi A.T. Hunder G.G. Lie J.T. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis) Arthritis Rheum. 33 1990 1094 1990 \n3 Neumann T. Manger B. Schmid M. Cardiac Involvement in churg-strauss syndrome Medicine 88 2009 236 243 19593229 \n4 Comarmond C. Pagnoux C. Khellaf M. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group Cohort Arthritis Rheum. 65 2013 270 281 23044708 \n5 Ali A.K. Hartzema A. Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting J. Asthma Allergy 5 2012 1 9 22690127 \n6 Sablé-Fourtassou R. Mahr A. Pagnoux C. Antineutrophil cytoplasmatic antibodies and the churg-strauss syndrome Ann. Intern. Med. 143 2005 632 638 16263885 \n7 Rosenberg M. Lorenz Gassler N. Rapid progressive eosinophilic cardiomyopathy in a patient with churg-strauss syndrome (CSS) Clin. Res. Cardiol. 95 2006 289 294 16598400 \n8 Sidhu B. Nanda U. Abbas S. Is this an exacerbation of asthma? a cautionary tale BMJ Case Rep. 2013 \n9 Ungprasert P. Cheungpasitporn W. Is it acute coronary syndrome or churg-strauss syndrome? Am. J. Emerg. Med. 31 2013 270.e5-270.e8 \n10 Kakuoros N. Bastiaenen R. Kourliouros A. Anderson L. Churg-Strauss presenting as acute coronary syndrome: sometimes it's zebras BMJ Case Rep. 2011\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "19()", "journal": "Respiratory medicine case reports", "keywords": "Acute chest pain; Asthma; EGPA; Eosinophilic granulomatosis with polyangiitis", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "94-7", "pmc": null, "pmid": "27625985", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "24072836;25971154;22690127;16598400;19593229;22809775;23044708;16263885;2202307;22700996", "title": "Think twice - Diagnostic delay in a patient with acute chest pain.", "title_normalized": "think twice diagnostic delay in a patient with acute chest pain" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THEOPHYLLINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THEOPHYLLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomegaly", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BANG CL, PORSBJERG CM. THINK TWICE - DIAGNOSTIC DELAY IN A PATIENT WITH ACUTE CHEST PAIN. RESPIRATORY MEDICINE CASE REPORTS. 2016;19:94-7", "literaturereference_normalized": "think twice diagnostic delay in a patient with acute chest pain", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20161010", "receivedate": "20160915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12754682, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "Inhibitors of tumor necrosing factor alpha (TNF-a) have proven to be highly effective in the treatment of rheumatoid arthritis (RA). Concerns, however, are raised about the possible association between these treatments and an increased development of malignancies. The objective of this paper was to compare the risk of hematologic and solid malignancies in patients treated for RA with anti-TNF therapy, with the risk in the general population. From January 2000 until January 2012, all RA patients that started treatment with anti-TNF agents were included in this single-center cohort study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. In our cohort of 365 patients, 34 malignancies were discovered in 30 patients after the start of anti-TNF treatment; 20 patients developed a solid malignancy, 6 a hematologic, 2 a solid and a hematologic malignancy, and 2 patients developed 2 solid malignancies. The overall incidence rate (IR) of malignancy was 1379.1 per 100.000 patient years. The risk or standardized incidence ratio (SIR) of solid malignancy, calculated by comparison with the age-adjusted population in Flanders, was 120.1 in female and 136.7 in male patients. The calculated SIR of hematologic malignancy was 450.8 for women and 473.9 for men. Some immune modulation-related lymphoproliferative disorders regressed spontaneously when stopping TNF blockers. Overall, the malignancy risk in our rheumatoid arthritis patients treated with anti-TNF therapy was slightly higher than in the normal population; the risk of hematologic malignancies was more important.", "affiliations": "Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. nathaliebergh@hotmail.com.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. laure-anne@teuwen.com.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. rene.westhovens@uzleuven.be.;Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.verschueren@uzleuven.be.", "authors": "Berghen|Nathalie|N|;Teuwen|Laure-Anne|LA|;Westhovens|Rene|R|;Verschueren|Patrick|P|", "chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept", "country": "Germany", "delete": false, "doi": "10.1007/s10067-015-3026-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0770-3198", "issue": "34(10)", "journal": "Clinical rheumatology", "keywords": "Cyclic citrullinated peptide; Malignancies; Rheumatoid arthritis; TNF-a", "medline_ta": "Clin Rheumatol", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015897:Comorbidity; D000068800:Etanercept; D005260:Female; D006801:Humans; D015994:Incidence; D000069285:Infliximab; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011446:Prospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult", "nlm_unique_id": "8211469", "other_id": null, "pages": "1687-95", "pmc": null, "pmid": "26219489", "pubdate": "2015-10", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "17922666;16508929;8051534;22357455;22241900;17469100;21701623;21570495;20870100;22766000;22945500;21572154;16705109;15547182;23560463;11961039;21701636;20064207;19767727;19147611;23442063;21898354;18433475;18378514;21148156;16947774;20810498;22166850;18155297;12687538;18853167;17729297;21885875;10071343", "title": "Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study.", "title_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study" }

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MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY. 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MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY.. 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MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY. 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MALIGNANCIES AND ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS: A SINGLE-CENTER OBSERVATIONAL COHORT STUDY.. CLIN-RHEUMATOL. 2015?34(10):1687-95", "literaturereference_normalized": "malignancies and anti tnf therapy in rheumatoid arthritis a single center observational cohort study", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151207", "receivedate": "20151207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11809031, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "BACKGROUND\nMirabegron, a β3 adrenergic receptor agonist, is FDA approved for treatment of overactive bladder. Approved in 2012 in the US, there have been no reports of any effects of mirabegron on pulmonary function.\n\n\nMETHODS\nWe report the case of a 65 year old male with a history of Parkinson's disease, OSA, and aspiration pneumonia presenting with subacute worsening dyspnea and found to have worsening restrictive ventilatory defect with a pattern consistent with neuromuscular weakness. After recalling that initiation of mirabegron correlated with onset of his worsening symptoms, the patient decided to perform a trial period off the drug. He subsequently reported prompt improvement in his respiratory symptoms, which was confirmed objectively by pulmonary function tests. In this case, mirabegron was temporally associated with subacute worsening of the patient's pulmonary restrictive physiology, with subsequent resolution after discontinuation of the medication.\n\n\nCONCLUSIONS\nThe mechanism of this adverse effect is unknown, but we speculate that this effect may be potentially mediated by the effect of β3 adrenergic receptor agonism on skeletal muscle, in this case in a patient with pre-existing neuromuscular disease. Careful assessment of patients who develop shortness of breath while on mirabegron should include an assessment for restrictive lung disease secondary neuromuscular dysfunction. Additional study is needed of the effects of β3 agonism on skeletal muscle.", "affiliations": "Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 676 North St. Clair, Arkes Pavilion Suite 1400 Chicago, IL 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-341, Chicago, IL 60611, USA.;Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USA.", "authors": "Malsin|Elizabeth S|ES|;Coleman|John M|JM|;Wolfe|Lisa F|LF|;Lam|Anna P|AP|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2019.02.012", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30003-610.1016/j.rmcr.2019.02.012Case ReportRespiratory dysfunction following initiation of mirabegron: A case report Malsin Elizabeth S. Elizabeth.malsin@northwestern.edua∗Coleman John M. colemanjm@northwestern.edubWolfe Lisa F. lwolfe@northwestern.educLam Anna P. lam4@northwestern.eduaa Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-349 Chicago, Illinois 60611, USAb Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 676 North St. Clair, Arkes Pavilion Suite 1400 Chicago, IL 60611, USAc Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, 240 East Huron Street, McGaw Pavilion, Suite M-341, Chicago, IL 60611, USA∗ Corresponding author. Elizabeth.malsin@northwestern.edu16 2 2019 2019 16 2 2019 26 304 306 4 1 2019 12 2 2019 15 2 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background: Mirabegron, a β3 adrenergic receptor agonist, is FDA approved for treatment of overactive bladder. Approved in 2012 in the US, there have been no reports of any effects of mirabegron on pulmonary function.\n\nCase presentation: We report the case of a 65 year old male with a history of Parkinson's disease, OSA, and aspiration pneumonia presenting with subacute worsening dyspnea and found to have worsening restrictive ventilatory defect with a pattern consistent with neuromuscular weakness. After recalling that initiation of mirabegron correlated with onset of his worsening symptoms, the patient decided to perform a trial period off the drug. He subsequently reported prompt improvement in his respiratory symptoms, which was confirmed objectively by pulmonary function tests. In this case, mirabegron was temporally associated with subacute worsening of the patient's pulmonary restrictive physiology, with subsequent resolution after discontinuation of the medication.\n\nConclusions: The mechanism of this adverse effect is unknown, but we speculate that this effect may be potentially mediated by the effect of β3 adrenergic receptor agonism on skeletal muscle, in this case in a patient with pre-existing neuromuscular disease. Careful assessment of patients who develop shortness of breath while on mirabegron should include an assessment for restrictive lung disease secondary neuromuscular dysfunction. Additional study is needed of the effects of β3 agonism on skeletal muscle.\n\nKeywords\nNeuromuscular lung diseaseAdverse medication effectβ3 receptor agonist therapy\n==== Body\n1 Background\nMirabegron is a β3-adrenergic receptor agonist prescribed for overactive bladder. While several β3 agonists have been developed, only mirabegron is FDA approved. The most commonly reported adverse effects of mirabegron include hypertension, tachycardia, headache, dizziness, constipation, diarrhea, abdominal pain, back pain, arthralgias and sinusitis. The only pulmonary complication reported was development of a pulmonary neoplasm. We report a case of a patient who developed restrictive ventilatory defect following the initiation of mirabegron.\n\n2 Case presentation\nOur patient is a 65 year-old man with a history of Parkinson's disease, obstructive sleep apnea on CPAP, and aspiration pneumonia. His medications include mirabegron, finasteride, pramipexole, albuterol as needed, modafinil, carbidopa-levodopa, metformin, multivitamins, and ibuprofen as needed. In July 2017, he presented with increased dyspnea on exertion. He noted worsening dyspnea for several weeks, with progression to dyspnea with activities of daily living. He denied constitutional symptoms, including changes in his physical strength, muscle spasms or worsening tremor. His vital signs were unremarkable; exam was notable for mild diaphoresis and dyspnea at rest, but a normal lung exam.\n\nPulmonary function tests (PFT) revealed decline in seated forced expiratory volume in 1 s (FEV1) to 3.10 L (78% predicted) from 4.13 L (92%) two years prior; decline in forced vital capacity (FVC) 3.79 L (72%) from 4.95 L (102%); FEV1/FVC ratio 82%, and total lung capacity (TLC) 7.17L (90%, from 7.99L (105%)), with a normal diffusion capacity of carbon monoxide (DLco) of 26.9 mL/mmHg/minute (93%). Also notable were supine FVC 3.43L (65%) and FEV1 2.72 L (69%). Seated maximal inspiratory pressure (MIP) was 69 cm H2O (64%) and maximal expiratory pressure (MEP) was 77 (38%). High-resolution computed tomography scan of the chest showed ground glass opacities in the right lower lobe, stable 3 mm nodule in the left lower lobe, and stable moderate air trapping. The patient was initiated on a bronchial hygiene regimen and sent for follow-up with his neurologist given concern for the patient's Parkinson's disease contributing to new onset neuromuscular respiratory disease, given the pattern of limitation on his PFT.\n\nHis dyspnea persisted the following month. After viewing a television commercial for mirabegron warning of possible adverse effect of shortness of breath (due to anaphylaxis), the patient correlated initiation of mirabegron for urinary urgency with the start of his symptoms, and self-discontinued his mirabegron. He returned to clinic six weeks later and reported subjective improvement of his dyspnea. His urinary urgency was noted to be at previous baseline and was deemed tolerable by the patient. He again noted no other changes to his baseline Parkinson's symptoms.\n\nOffice spirometry demonstrated increases in supine FEV1 to 4.73 mL (+13%) and maximal expiratory pressure to 102 cm (+24%). Four months later, FVC improved to 4.09L (78%) and TLC to 7.94L (108%). While the temporal relationship between the use and discontinuation of mirabegron with the patient's symptoms and change in lung function suggests respiratory muscle pathology without symptoms of simultaneous non-respiratory muscle weakness, the mechanism by which β3-adrenergic receptor agonism could cause respiratory dysfunction has not been described.\n\n3 Discussion\nAfter caring for this patient, the authors reviewed the known physiology and pathology, as well as the literature, regarding potential mechanisms behind the development of symptomatic neuromuscular respiratory illness after the initiation of mirabegron. To our knowledge, there is no report in the literature of this potential adverse effect. However, our review did identify potential pathophysiologic mechanisms.\n\nThree known subtypes of β-adrenergic receptors (β-AR) exist, with the β3-adrenergic receptor (ADRB3) found in multiple tissues and constituting the predominant β-AR in the detrusor muscles of the bladder [1,2]. From RNA-Sequencing analysis and the Human Protein Atlas (dataset, highest expression levels of ADRB3 are in the ovary at 10 transcripts per million (TPM), gallbladder (2.6 TPM), and smooth muscle (1.4 TPM). Other tissues have minimal expression, including lung tissue (0.1 TPM) and skeletal muscle (0 TPM) [3,4]. However, immunostaining using the high-affinity monoclonal antibody Mab72c demonstrates β3-receptors in skeletal muscle, adipose tissue, and myocardial tissue [5].\n\nβ1-and β2-adrenergic receptors, Gs-linked receptors, when activated by catecholamines mediate a rise in cyclic-AMP resulting in activation of protein kinase A [6,7]. Multiple studies have demonstrated a different mechanism for the β3-AR, including activity via the mTOR and Gi-nitric oxide synthetase (NOS) pathways [8,9]. Studies revealing stimulation of β-AR in skeletal muscle produces anabolic effects, likely via a crucial role in protein metabolism, have spurred interest in the therapeutic potential of β-AR agonists in muscular pathologies [[10], [11], [12]]. Puzzo and colleagues demonstrated β3-receptor agonism significantly increases muscle force production and myofiber area, and decreases muscle fiber stiffness [13], similar to previous reports of β2-AR agonism, in fast-twitch fibers [14]. The novel finding that β3-agonism decreased stiffness of muscle fibers has potential implications for diseases with high muscle stiffness, including muscle dystrophies.\n\nThe majority of patients with Parkinson's disease have muscle rigidity, which can affect any skeletal muscle. Baclofen, a gamma-aminobutyric acid (GABA)-receptor agonist, is used to treat spasticity and dystonia in Parkinson's disease. Hypotonia is the most common adverse reaction, occurring in 2.4–34.7% of patients receiving intrathecal baclofen during trials [15]. Muscular weakness has also been reported in patients on oral baclofen for spasticity [16,17]. Baclofen impacts control of ventilation and can cause central apnea events [18], with overdose reported to cause flaccid paralysis and respiratory depression [19,20].\n\nIn our patient with Parkinson's disease, we speculate β3-agonism of mirabegron may have had similar effects as baclofen overdose and may have acted synergistically with baclofen, resulting in decreased stiffness of respiratory muscles and worsened lung function. In light of the findings of Puzzo et al., [13] further research is needed to elucidate effects of β3-AR agonism in muscles, and mirabegron should be closely monitored in patients with neurodegenerative and neuromuscular diseases.\n\nEthics approval\nNot applicable.\n\nConsent for publication\nObtained from patient (adult).\n\nAvailability of data and materials\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nConflicts of interest\nThe authors declare that they have no competing interests.\n\nAuthor contributions\nESM, JMC, AIL analyzed and interpreted patient data. ESM wrote the manuscript with JMC, AIL, LFW contributing equally to its final form. All authors read and approved the final manuscript.\n\nFunding\nDr. Malsin is funded in part via NIH institutional T32 –HL076139.\n\nAbbreviations:\nPFTpulmonary function tests\n\nFEV1forced expiratory volume in one second\n\nFVCforced vital capacity\n\nFEV1/FVCratio of forced expiratory volume in 1 s to forced vital capacity\n\nTLCtotal lung capacity\n\nDLcodiffusion capacity of carbon monoxide\n\nMIPmaximal inspiratory pressure\n\nMEPmaximal expiratory pressure\n\nβ-ARβ-adrenergic receptors\n\nTPMtranscripts per million\n\nGABAgamma-aminobutyric acid\n\n\n\nAcknowledgements\nnot applicable.\n==== Refs\nReferences\n1 Igawa Y. Aizawa N. Homma Y. Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder Kor. J. Urol. 51 12 2010 811 818 \n2 Ochodnicky P. Uvelius B. Andersson K.E. Michel M.C. Autonomic nervous control of the urinary bladder Acta Physiol. (Oxf). 207 1 2013 16 33 23033838 \n3 Fagerberg L. Hallstrom B.M. Oksvold P. Kampf C. Djureinovic D. Odeberg J. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics Mol. Cell. Proteomics 13 2 2014 397 406 24309898 \n4 Uhlen M. Oksvold P. Fagerberg L. Lundberg E. Jonasson K. Forsberg M. Towards a knowledge-based human protein Atlas Nat. Biotechnol. 28 12 2010 1248 1250 21139605 \n5 Chamberlain P.D. Jennings K.H. Paul F. Cordell J. Berry A. Holmes S.D. The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle Int. J. Obes. Relat. Metab. Disord. 23 10 1999 1057 1065 10557026 \n6 Strosberg A.D. Structure, function, and regulation of adrenergic receptors Protein Sci. 2 8 1993 1198 1209 8401205 \n7 Wachter S.B. Gilbert E.M. Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application Cardiology 122 2 2012 104 112 22759389 \n8 Roberts S.J. Summers R.J. Cyclic AMP accumulation in rat soleus muscle: stimulation by β2- but not β3-adrenoceptors Eur. J. Pharmacol. 348 1 1998 53 60 9650831 \n9 Gauthier C. Leblais V. Kobzik L. Trochu J.N. Khandoudi N. Bril A. The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle J. Clin. Invest. 102 7 1998 1377 1384 9769330 \n10 Kim Y.S. Sainz R.D. Beta-adrenergic agonists and hypertrophy of skeletal muscles Life Sci. 50 6 1992 397 407 1346465 \n11 Lynch G.S. Ryall J.G. Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease Physiol. Rev. 88 2 2008 729 767 18391178 \n12 Mersmann H.J. Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action J. Anim. Sci. 76 1 1998 160 172 9464897 \n13 Puzzo D. Raiteri R. Castaldo C. Capasso R. Pagano E. Tedesco M. CL316,243, a beta3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength Sci. Rep. 5 2016 37504 27874066 \n14 Zeman R.J. Ludemann R. Easton T.G. Etlinger J.D. Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a beta 2-receptor agonist Am. J. Physiol. 254 6 Pt 1 1988 E726 E732 3377073 \n15 Lioresal (Baclofen) Injection Package Insert 2016 Saol Therapeutics, Inc. Roswell, GA \n16 Baclofen Tablet Package Insert 2016 Lannett Company, Inc. Philadelphia, PA \n17 Dario A. Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity Drug Saf. 27 11 2004 799 818 15350152 \n18 Olivier P.Y. Joyeux-Faure M. Gentina T. Launois S.H. d'Ortho M.P. Pepin J.L. Severe central sleep apnea associated with chronic baclofen therapy: a case series Chest 149 5 2016 e127 e131 27157226 \n19 Caron E. Morgan R. Wheless J.W. An unusual cause of flaccid paralysis and coma: baclofen overdose J. Child Neurol. 29 4 2014 555 559 23481445 \n20 Stroud J. Scattoloni J. Blasingim M. Nafiu O.O. Intrathecal baclofen toxicity: an unusual cause of paediatric postoperative coma and respiratory depression Eur. J. Anaesthesiol. 31 6 2014 334 336 24557024\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "26()", "journal": "Respiratory medicine case reports", "keywords": "Adverse medication effect; Neuromuscular lung disease; β3 receptor agonist therapy", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "304-306", "pmc": null, "pmid": "30886821", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "10557026;1346465;15350152;18391178;21139605;21221199;22759389;23033838;23481445;24309898;24557024;27157226;27874066;3377073;8401205;9464897;9650831;9769330", "title": "Respiratory dysfunction following initiation of mirabegron: A case report.", "title_normalized": "respiratory dysfunction following initiation of mirabegron a case report" }

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{ "abstract": "Women with epilepsy have a higher risk of having dysmorphic child. We report on a child exposed prenatally to valproate and carbamazepine presenting with severe bilateral upper limb defect and phenotypic features of fetal valproate syndrome. Anticonvulsant drugs can cause severe birth defects, especially when used in combination.", "affiliations": "Department of Obstetrics and Gynecology, Kahramanmaras Sutcuimam University, Turkey. mguven@ksu.edu.tr", "authors": "Guven|Melih Atahan|MA|;Batukan|Cem|C|;Ceylaner|Serdar|S|;Ceylaner|Gülay|G|;Uzel|Murat|M|", "chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid", "country": "England", "delete": false, "doi": "10.1080/14767050500420665", "fulltext": null, "fulltext_license": null, "issn_linking": "1476-4954", "issue": "19(2)", "journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians", "keywords": null, "medline_ta": "J Matern Fetal Neonatal Med", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D002220:Carbamazepine; D004827:Epilepsy; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital; D011247:Pregnancy; D014635:Valproic Acid", "nlm_unique_id": "101136916", "other_id": null, "pages": "115-7", "pmc": null, "pmid": "16676441", "pubdate": "2006-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of fetal anticonvulsant syndrome with severe bilateral upper limb defect.", "title_normalized": "a case of fetal anticonvulsant syndrome with severe bilateral upper limb defect" }

[ { "companynumb": "TR-ABBVIE-06P-161-0332583-00", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "018081", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Limb malformation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Limb hypoplasia congenital", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUVEN M, BATUKAN C, CEYLANDER S, ET AL. A CASE OF FETAL ANTICONVULSANT SYNDROME WITH SEVERE BILATERAL UPPER LIMB DEFECT. THE JOURNAL OF MATERNAL-FETAL AND NEONATAL MEDICINE. 2006 FEB;19(2):115-117.", "literaturereference_normalized": "a case of fetal anticonvulsant syndrome with severe bilateral upper limb defect", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "FR", "receiptdate": "20170705", "receivedate": "20170705", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13718647, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" } ]

{ "abstract": "BACKGROUND\nKoebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event.\n\n\nOBJECTIVE\nTo study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal.\n\n\nMETHODS\nWe assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR.\n\n\nRESULTS\nAll lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls.\n\n\nCONCLUSIONS\nWe observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.", "affiliations": "Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany.", "authors": "Gambichler|T|T|;Rüddel|I|I|;Hessam|S|S|;Bechara|F G|FG|;Stockfleth|E|E|;Schmitz|L|L|", "chemical_list": "C540838:5-hydroxymethyl-2'-deoxycytidine; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D044503:5-Methylcytosine; C538784:IDH2, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000069462:Dimethyl Fumarate; D001379:Azathioprine", "country": "England", "delete": false, "doi": "10.1111/jdv.14887", "fulltext": null, "fulltext_license": null, "issn_linking": "0926-9959", "issue": "32(9)", "journal": "Journal of the European Academy of Dermatology and Venereology : JEADV", "keywords": null, "medline_ta": "J Eur Acad Dermatol Venereol", "mesh_terms": "D044503:5-Methylcytosine; D001379:Azathioprine; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D000069462:Dimethyl Fumarate; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007521:Isocitrate Dehydrogenase; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D009364:Neoplasm Recurrence, Local; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D012867:Skin; D012878:Skin Neoplasms; D012879:Skin Physiological Phenomena; D016159:Tumor Suppressor Protein p53", "nlm_unique_id": "9216037", "other_id": null, "pages": "1485-1491", "pmc": null, "pmid": "29478287", "pubdate": "2018-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery.", "title_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery" }

[ { "companynumb": "DE-MYLANLABS-2018M1068147", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA FG, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. J?EUR?ACAD?DERMATOL?VENEREOL 2018?32(9):1485?1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180924", "receivedate": "20180924", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15417744, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "DE-BIOGEN-2017BI00458203", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 13 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte count decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neoplasm skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY. 2018?32(9):1485-1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181116", "receivedate": "20170918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13981984, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "DE-BIOGEN-2018BI00538186", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 13 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte count decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY + VENEREOLOGY.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180314", "receivedate": "20180314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14634674, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "DE-BIOGEN-2018BI00538183", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR OVER 15 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Squamous cell carcinoma of skin", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphocyte percentage decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bowen^s disease", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Actinic keratosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA F, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. DOI: 10.1111/JDV.14887. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181116", "receivedate": "20180315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14642557, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "DE-MYLANLABS-2018M1068061", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DIMETHYL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TECFIDERA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Squamous cell carcinoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Koebner phenomenon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAMBICHLER T, RUDDEL I, HESSAM S, BECHARA FG, STOCKFLETH E, SCHMITZ L. ALTERED EPIGENETIC PATHWAYS AND CELL CYCLE DYSREGULATION IN HEALTHY APPEARING SKIN OF PATIENTS WITH KOEBNERIZED SQUAMOUS CELL CARCINOMAS FOLLOWING SKIN SURGERY. J?EUR?ACAD?DERMATOL?VENEREOL 2018?32(9):1485?1491.", "literaturereference_normalized": "altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180925", "receivedate": "20180925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15423915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Colon and rectal lymphomas are rare and can occur in the context of posttransplant lymphoproliferative disorder. Evidence-based management guidelines are lacking.\n\n\n\nThe purpose of this study was to characterize the presentation, diagnosis, and management of colorectal lymphoma and to identify differences within the transplant population.\n\n\n\nThis was a retrospective review of patients evaluated for colorectal lymphoma between 2000 and 2017. Patients were identified through clinical note queries.\n\n\n\nFour hospitals within a single health system were included.\n\n\n\nFifty-two patients (64% men; mean age = 64 y; range, 26-91 y) were identified. No patient had <3 months of follow-up. Eight patients (15%) had posttransplant lymphoproliferative disorder.\n\n\n\nOverall survival, recurrence, and complications in treatment pathway were measured.\n\n\n\nMost common presentations were rectal bleeding (27%), abdominal pain (23%), and diarrhea (23%). The most common location was the cecum (62%). Most frequent histologies were diffuse large B-cell lymphoma (48%) and mantle cell lymphoma (25%). Posttransplant lymphoproliferative disorder occurred in the cecum (n = 4) and rectum (n = 4). Twenty patients (38%) were managed with chemotherapy; 25 patients (48%) underwent primary resection. Mass lesions had a higher risk of urgent surgical resection (35% vs 8%; p = 0.017). Three patients (15%) treated with chemotherapy presented with perforation requiring emergency surgery. Overall survival was 77 months (range, 25-180 mo). Patients with cecal involvement had longer overall survival (96 vs 26 mo; p = 0.038); immunosuppressed patients had shorter survival (16 vs 96 mo; p = 0.006). Survival in patients treated with surgical management versus chemotherapy was similar (67 vs 105 mo; p = 0.62).\n\n\n\nThis was a retrospective chart review, with data limited by the contents of the medical chart. This was a small sample size.\n\n\n\nColorectal lymphoma is rare, with variable treatment approaches. Patients with noncecal involvement and chronic immunosuppression had worse overall survival. Patients with mass lesions, particularly cecal masses, are at higher risk to require urgent intervention, and primary resection should be considered. See Video Abstract at http://links.lww.com/DCR/A929.", "affiliations": "Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Medical School, University of Minnesota, Minneapolis, Minnesota.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.;Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota.;Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Surgery, University of California Los Angeles, Los Angeles, California.", "authors": "Skube|Steven J|SJ|;Arsoniadis|Elliot G|EG|;Sulciner|Megan L|ML|;Gilles|Scott R|SR|;Gaertner|Wolfgang B|WB|;Madoff|Robert D|RD|;Melton|Genevieve B|GB|;Peterson|Bruce A|BA|;Kwaan|Mary R|MR|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/DCR.0000000000001373", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-3706", "issue": "62(6)", "journal": "Diseases of the colon and rectum", "keywords": null, "medline_ta": "Dis Colon Rectum", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "0372764", "other_id": null, "pages": "694-702", "pmc": null, "pmid": "30870226", "pubdate": "2019-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Colorectal Lymphoma: A Contemporary Case Series.", "title_normalized": "colorectal lymphoma a contemporary case series" }

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{ "abstract": "Radiation therapy of neoplasms involving the chest or mediastinum results in a wide spectrum of cardiac complications including coronary artery disease, which can present in patients with few or no traditional cardiac risk factors. We report a case of radiation induced coronary artery disease in a 60-year-old female with a history of stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier and treated with chemotherapy and radiotherapy. She presented to the hospital with atypical chest pain that had occurred intermittently over the preceding week. Her initial electrocardiogram and cardiac enzymes were within normal limits. However, following an indeterminate exercise nuclear stress test, she developed chest pain and elevated cardiac enzymes. Coronary angiography demonstrated 90% stenosis of the left main coronary artery ostium, without any evidence of atherosclerotic disease or stenosis in other coronary arteries. She underwent surgical revascularization, which revealed dense adhesions surrounding the heart. During surgery, she developed severe bleeding and died. Coronary artery disease can present within years of radiation exposure, and ostial lesions are typical. Treatment is often challenging because of the effects of radiation on other tissues and the risks of revascularization procedures. Therefore, a multidisciplinary team approach should be considered.", "affiliations": "Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA.;Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USA.", "authors": "Alsara|Osama|O|;Alsarah|Ahmad|A|;Kalavakunta|Jagadeesh K|JK|;Laird-Fick|Heather|H|;Abela|George S|GS|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2013/834164", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/834164Case ReportIsolated Left Main Coronary Artery Stenosis after Thoracic Radiation Therapy: To Operate or Not to Operate Alsara Osama \n1\n*Alsarah Ahmad \n1\nKalavakunta Jagadeesh K. \n2\nhttp://orcid.org/0000-0001-9215-8152Laird-Fick Heather \n1\nAbela George S. \n2\n1Michigan State University, Department of Internal Medicine, B-301 Clinical Center, East Lansing, MI 48824, USA3Michigan State University, Division of Cardiovascular Disease, B-208 Clinical Center, East Lansing, MI 48824, USA*Osama Alsara: osama.alsara@hc.msu.eduAcademic Editor: Bruno Megarbane\n\n2013 12 12 2013 2013 83416420 6 2013 6 11 2013 Copyright © 2013 Osama Alsara et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Radiation therapy of neoplasms involving the chest or mediastinum results in a wide spectrum of cardiac complications including coronary artery disease, which can present in patients with few or no traditional cardiac risk factors. We report a case of radiation induced coronary artery disease in a 60-year-old female with a history of stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier and treated with chemotherapy and radiotherapy. She presented to the hospital with atypical chest pain that had occurred intermittently over the preceding week. Her initial electrocardiogram and cardiac enzymes were within normal limits. However, following an indeterminate exercise nuclear stress test, she developed chest pain and elevated cardiac enzymes. Coronary angiography demonstrated 90% stenosis of the left main coronary artery ostium, without any evidence of atherosclerotic disease or stenosis in other coronary arteries. She underwent surgical revascularization, which revealed dense adhesions surrounding the heart. During surgery, she developed severe bleeding and died. Coronary artery disease can present within years of radiation exposure, and ostial lesions are typical. Treatment is often challenging because of the effects of radiation on other tissues and the risks of revascularization procedures. Therefore, a multidisciplinary team approach should be considered.\n==== Body\n1. Introduction\nFor the past few decades, radiation has been used effectively in the treatment of neoplasms involving the chest and mediastinum, including breast cancer, lymphomas, and lung cancer. However, radiotherapy of the chest can have a number of cardiac complications including pericarditis, pericardial effusions, conduction disorders, pancarditis, functional valvular defects, and coronary artery disease (CAD) [1]. CAD has been reported more commonly with Hodgkin's lymphoma, presumably because these patients tend to be younger and survive longer [2]. In this report we describe a 60-year-old woman with isolated left main coronary ostial stenosis diagnosed eight years after chest irradiation performed for stage IIIA nonsmall cell lung cancer. This case emphasizes the importance of clinical suspicion, prognostication, and the balancing risks and benefits of competing therapies.\n\n2. Case Presentation\nA 60-year-old woman with a history of lung cancer currently in remission was admitted with complaints of chest pain. She had recurrent substernal chest pain, increasing in severity, without radiation or associated symptoms during the preceding week. She denied any specific alleviating or provoking factors.\n\nPast medical history was significant for hypertension and stage IIIA nonsmall cell lung carcinoma which was diagnosed eight years earlier. She had been treated with chemotherapy and radiotherapy. One year later she developed a malignant pericardial effusion, treated with a pericardial window, and recurrent pleural effusions, which were drained with pleural catheters. During the next six years, she was in full remission as confirmed by annual chest computed tomography (CT). Her medications included aspirin, metoprolol, iron, vitamin B12, and gefitinib. She was a nonsmoker and drinks alcohol occasionally.\n\nAt presentation, her physical exam was benign. Initial cardiac biomarkers (creatine phosphokinase, troponin) and fasting lipid panel were within normal limits. The 12-lead electrocardiogram (ECG) showed normal sinus rhythm without any significant ST-T changes. Chest radiograph showed left perihilar parenchymal scars, surgical clips, and postoperative changes in the chest (Figure 1). Other laboratory studies, including two more sets of cardiac biomarkers, were normal.\n\nShe underwent an exercise nuclear stress test which demonstrated indeterminate electrocardiogram (ECG) changes with a small anteroseptal wall defect which appeared to be artifactual. Following the stress test, she developed retrosternal chest pain. Although her ECG did not show any acute changes, repeat serum troponin level was elevated at 0.42 ug/L. Coronary angiography was performed and demonstrated 90% stenosis of the left main coronary artery ostium, dominant right coronary artery, and no evidence of any atherosclerotic disease or stenosis in other coronary arteries (Figures 2, 3, and 4). Left ventricular ejection fraction was 55% without any regional wall motion abnormalities.\n\nSyntax score was calculated to be 12% which predicts comparable outcomes of surgical and angioplastic procedures. Taking into consideration patient's history that may complicate the surgical treatment including her previous surgical interventions, radiation therapy, and chemical therapy, the interventional cardiology team recommended percutaneous coronary intervention (PCI) with stenting of the lesion. Cardiothoracic surgeons were consulted as well for further evaluation and they agreed that surgery will be challenging in this patient, but at the same time they felt that she may tolerate the surgery well, given her functional status, remission from cancer, and the low operative risk (EuroScore is 1.23%), and they suggested coronary artery bypass graft (CABG) surgery as a reasonable option due to the high failure rate of stenting ostial lesions and to avoid the possible cardiac arrest associated with the intervention on the stenotic ostium of left main coronary artery.\n\nAfter discussing both treatment options, the risks and benefits of each procedure with the patient, she decided to undergo surgical revascularization. Overnight, she experienced excruciating anginal chest pain without any elevation in cardiac enzymes; as a result she was taken to surgery the next day.\n\nIntraoperatively she was noted to have dense adhesions surrounding the heart. As a result, she developed severe bleeding from the adhesions. Despite aggressive transfusion of red blood cells and platelets, bleeding could not be controlled and she died during surgery. The family refused to allow autopsy to confirm the diagnosis.\n\n3. Discussion\nThis is a case of a 60-year-old female with no classic cardiac risk factors, who developed a stenosis in the ostium of left main coronary artery eight years after undergoing radiation therapy for nonsmall cell lung cancer. She went to the operating room for CABG due to recurrent unstable angina but developed fatal bleeding related to side effects of both radiation and chemotherapy.\n\nThoracic irradiation can result in injury or inflammation of any of the cardiac structures. CAD has been reported in 5.5–12% of patients undergoing therapeutic chest radiotherapy, usually manifesting 3–30 years after radiation exposure [3]. Histology of coronary artery tissues obtained from affected patients have demonstrated intimal thickening with minimal extracellular lipid deposits [4]. Although the mechanism of radiation induced CAD (RICAD) is not fully understood, it is believed that radiation may stimulate cytokines and growth factors which in turn induce fibrosis and obstruction [5].\n\nOstial stenosis is typical of RICAD, since the vessels' openings are usually at the center of the radiation field. One study found that 16% of isolated coronary ostial stenosis was secondary to radiation therapy [6]. Isolated ostial stenosis of the left main coronary artery following radiation therapy has been reported in eight other cases in the literature [7–14] (Table 1). These patients were young to middle-aged females (mean age 40 years, range 26–51 years), with no or few traditional risk factors for CAD. Most presented with typical angina, between 2 and 20 years after radiotherapy. Our patient was older than those previously reported and developed symptoms eight years after therapy. Since RICAD presents about 16 years after radiation exposure and the 5 year survival life in patients with stage IIIA nonsmall cell lung cancer is estimated to be between 9 and 25%, it is very rare to see RICAD in this group [1, 15].\n\nThe strategy for revascularization of RICAD is typically the same as for atherosclerotic CAD [1]. Traditionally, CABG has been considered the treatment of choice for left main coronary artery disease (LMCAD) due to its role in increasing the life expectancy in patients with significant stenosis [16, 17]. The left internal mammary artery (LIMA) is typically used as a bypass conduit. Despite concerns that radiation might damage the LIMA, increase its fragility, and lead to early graft failure [18, 19], recent studies have documented patency rates comparable to that of venous grafts at 5 year follow-up [20, 21], making LIMA grafting a viable option for RICAD as well. Yet cardiac surgery in patients with past chest irradiation can still be technically challenging, with a greater risk of perioperative complications in the presence of pericardial thickening and retrosternal fibrosis. Although an early study has showed good outcomes of CABG treatments in patients with mediastinal radiation therapy, Wu et al. have found recently that patients with radiation induced heart disease have greater short-term and long-term mortality after cardiovascular surgeries compared to patients in same age and sex who underwent similar surgeries [22, 23]. This study also showed that the standard preoperative risk scores are usually suboptimal in predicting mortality of cardiac surgeries in patients with radiation heart disease [23]. With this in mind, other treatment options such as PCI should always be considered.\n\nThere is a growing body of literature supporting PCI with stenting of LMCAD due to atherosclerosis. Some trials have yielded rates of myocardial infarction and mortality similar to CABG, but with better perioperative outcomes [24]. As a result, PCI is now considered an acceptable alternative to surgical revascularization in some patients with LMCAD [16, 25, 26]. This approach could be particularly attractive for patients with radiation-induced adhesions. Ostial stents, though, have been associated with higher rates of restenosis related to their increased risk for proximal or distal displacement [27]. Several new techniques may improve the precision of ostial stent positioning [28], but long-term outcome data are not yet available.\n\nOther comorbidities or medications may also influence the decision to choose percutaneous or surgical revascularization in patients with RICAD. For example, our patient was receiving the gefitinib, a chemotherapeutic agent which decreases platelet function via prostaglandin and thrombaxene and increases the bleeding risk [29]. There are no guidelines or studies on the perioperative management of patients receiving gefitinib. Its half-life is 48 hours, in contrast to 8 hours for the more common antiplatelet agents such as clopidogrel, so prolonged interruption of therapy may be necessary to decrease bleeding risk. We believe that additional preoperative evaluation by a hematologist-oncologist is warranted. Balancing the risk of bleeding against the risk of myocardial infarction or death becomes a complicated and imprecise calculus requiring the input of a multidisciplinary team.\n\nOur case is unique, in that our patient was older at presentation, underwent chest irradiation for lung cancer rather than lymphoma, developed isolated left main coronary ostial stenosis, and her management was complicated by the combined effects of radiation and chemotherapy. More importantly, this case emphasizes the importance of a multidisciplinary team approach and participatory decision making when faced with significant risks of available treatment options.\n\nDisclosure\nDrs. Alsara, Kalavakunta, Alsarah, and Laird-Fick have no relationships to disclose. Dr. Abela is a speaker of Merck, Abbott, and GlaxoSmithKline. Those relationships are not related to this paper.\n\nAcknowledgment\nDr. Abela is a recipient of grants from Merck and Novartis.\n\nFigure 1 Posterior to anterior chest X-ray shows left perihilar parenchymal scars, surgical clips, and postoperative changes in the chest.\n\nFigure 2 Coronary angiography with a right anterior oblique (RAO)/caudal projection. Arrow points to severe isolated ostial stenosis of left main coronary artery.\n\nFigure 3 Coronary angiography of left main coronary artery in the left anterior oblique (LAO) and caudal view showing severe isolated ostial stenosis (arrow).\n\nFigure 4 Coronary angiography of the right coronary artery in left anterior oblique (LAO) view.\n\nTable 1 Review of reported cases of isolated ostial stenosis of left main coronary artery following radiation therapy*.\n\nAuthors (year)\tGender\tAge (Y)\tRF\tNeoplasm\tLatency (Y)\tPresenting symptoms\t\nRadwaner et al. [7] (1987)\tF\t27\tNo\tHodgkin's lymphoma\t8\tAngina\t\nGrollier et al. [8] (1988)\tF\t50\tSmoking \tBreast cancer\t5\tAngina\t\nOrzan et al. [9] (1995)\tF\t26\tNo\tHodgkin's lymphoma\t10\tDyspnea, pleural effusion\t\nTakewa et al. [10] (1996)\tF\t45\t/\tThymic carcinoid\t3\tAngina\t\nBensaid et al. [11] (1998)\tF\t43\tNo\tHodgkin's lymphoma\t20\tMyocardial infarction \t\nCaus et al. [12] (1999)\tF\t47\tSmoking\tNH lymphoma\t3\tAngina\t\nVictor and Parente [13] (2004)\tF\t51\tDyslipidemia\tHodgkin's lymphoma\t2\tAngina\t\nKorosoglou et al. [14] (2012)\tF\t34\tNo\tNH lymphoma\t6\tAngina\t\n*F: female, Y: years, RF: risk factors for coronary artery disease, and NH: non-Hodgkin's.\n\nThe case of Takewa et al. [10] is in Japanese. The case of Bensaid et al. [11] is in French.\n==== Refs\n1 Veeragandham RS Goldin MD Surgical management of radiation-induced heart disease Annals of Thoracic Surgery 1998 65 4 1014 1019 2-s2.0-0031947823 9564920 \n2 Konings AW Smit Sibinga CT Aarnoudse MW de Wit SS Lamberts HB Initial events in radiation-induced atheromatosis. II. Damage to intimal cells Strahlentherapie 1978 154 11 795 800 2-s2.0-0018143851 715813 \n3 Miltenyi Z Keresztes K Garai I Radiation-induced coronary artery disease in Hodgkin’s disease Cardiovascular Radiation Medicine 2004 5 1 38 43 15275631 \n4 Dragomanovits SI Lazopoulos GL Tzinieris IN Deliargyris EN Coronary artery disease following mediastinal irradiation Hellenic Journal of Cardiology 2007 48 3 181 183 2-s2.0-34548033279 17629183 \n5 Yusuf SW Sami S Daher IN Radiation-induced heart disease: a clinical update Cardiology Research and Practice 2011 2011 9 pages 317659 \n6 Pilliere R Luquel L Brun D Jault F Gandjbakhch I Bourdarias JP Stenosis of the ostium of the left main coronary artery after mediastinal radiotherapy: a case report Archives des Maladies du Coeur et des Vaisseaux 1991 84 6 869 872 2-s2.0-0026179669 1898223 \n7 Radwaner BA Geringer R Goldmann AM Schwartz MJ Kemp HG Jr. Left main coronary artery stenosis following mediastinal irradiation American Journal of Medicine 1987 82 5 1017 1020 2-s2.0-0023614871 3578337 \n8 Grollier G Commeau P Mercier V Post-radiotherapeutic left main coronary ostial stenosis: clinical and histological study European Heart Journal 1988 9 5 567 570 2-s2.0-0023915199 3402473 \n9 Orzan F Bellis D Mollo F Brusca A Ostial stenosis of the left main coronary artery in a young woman 10 years after radiation therapy Cardiovascular Pathology 1995 4 1 69 71 2-s2.0-0028794975 25850782 \n10 Takewa Y Kawata T Yoshida Y Kawachi K Kitamura S Radiation-induced coronary ostial stenosis, a case of redo coronary bypass for the restenosis following patch angioplasty Nihon Kyobu Geka Gakkai Zasshi 1996 44 2 220 225 2-s2.0-0030080222 8717275 \n11 Bensaid J Benabbou M Goburdhun C Medard C Guillon A El Kenz A Ostial stenosis of the common trunk of the left coronary 20 years after mediastinal irradiation Annales de Cardiologie et d’Angeiologie 1998 47 10 732 734 2-s2.0-0032441956 \n12 Caus T Canavy I Mesana T Garcia E Raoul-Monties J Rescue revascularization for acute coronary occlusion late after radiotherapy Annals of Thoracic Surgery 1999 67 1 236 238 2-s2.0-0032989318 10086560 \n13 Victor EG Parente GB Mediastinal radiation therapy and occlusion of the ostium of the left main coronary artery Arquivos Brasileiros de Cardiologia 2004 82 3 295 300 2-s2.0-1642418088 15073656 \n14 Korosoglou G Kristen AV Andrassy M Katus HA Hardt SE Severe left main coronary stenosis in a young female patient, 6 years after mediastinal radiation therapy for non-Hodgkin lymphoma: assessment by coronary angiography and intravascular ultrasound Clinical Research in Cardiology 2012 101 4 317 320 2-s2.0-84856100084 22286318 \n15 Mountain CF Revisions in the international system for staging lung cancer Chest 1997 111 6 1710 1717 2-s2.0-0030912190 9187198 \n16 Wright RS Anderson JL Adams CD American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/Non–ST-elevation myocardial infarction : a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Journal of the American College of Cardiology 2011 57 19 e215 e367 2-s2.0-84860413284 21545940 \n17 Taggart DP Coronary artery bypass grafting is still the best treatment for multivessel and left main disease, but patients need to know Annals of Thoracic Surgery 2006 82 6 1966 1975 2-s2.0-33751233843 17126093 \n18 Hicks GL Jr. Coronary artery operation in radiation-associated atherosclerosis: long-term follow-up Annals of Thoracic Surgery 1992 53 4 670 674 2-s2.0-0026575538 1554280 \n19 Schulman HE Korr KS Myers TJ Left internal thoracic artery graft occlusion following mediastinal radiation therapy Chest 1994 105 6 1881 1882 2-s2.0-0028222239 8205898 \n20 Gansera B Schmidtler F Angelis I Quality of internal thoracic artery grafts after mediastinal irradiation Annals of Thoracic Surgery 2007 84 5 1479 1484 2-s2.0-35348970414 17954049 \n21 Brown ML Schaff HV Sundt TM Conduit choice for coronary artery bypass grafting after mediastinal radiation Journal of Thoracic and Cardiovascular Surgery 2008 136 5 1167 1171 2-s2.0-56249133492 19026798 \n22 Handa N McGregor CGA Danielson GK Coronary artery bypass grafting in patients with previous mediastinal radiation therapy Journal of Thoracic and Cardiovascular Surgery 1999 117 6 1136 1143 2-s2.0-0032970363 10343262 \n23 Wu W Masri A Popovic ZB Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study Circulation 2013 127 14 1476 1484 23569119 \n24 Dubois C Dens J Sinnaeve P Results of percutaneous coronary intervention of the unprotected left main coronary artery in 143 patients and comparison of 30-day mortality to results of coronary artery bypass grafting American Journal of Cardiology 2008 101 1 75 81 2-s2.0-37349002738 18157969 \n25 Park SJ Kim YH Park DW Randomized trial of stents versus bypass surgery for left main coronary artery disease New England Journal of Medicine 2011 364 18 1718 1727 2-s2.0-79955739237 21463149 \n26 Buszman PE Kiesz SR Bochenek A Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization Journal of the American College of Cardiology 2008 51 5 538 545 2-s2.0-38549139564 18237682 \n27 Dishmon DA Elhaddi A Packard K Gupta V Fischell TA High incidence of inaccurate stent placement in the treatment of coronary aorto-ostial disease Journal of Invasive Cardiology 2011 23 8 322 326 2-s2.0-80051987022 21828393 \n28 Kwan TW James D Huang Y Liou M Wong S Coppola J Perfection of precise ostial stent placement Journal of Invasive Cardiology 2012 24 7 354 358 22781478 \n29 Kanazawa S Yamaguchi K Kinoshita Y Muramatsu M Komiyama Y Nomura S Gefitinib affects functions of platelets and blood vessels via changes in prostanoids balance Clinical and Applied Thrombosis/Hemostasis 2005 11 4 429 434 2-s2.0-27544499208 16244768\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2013()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "834164", "pmc": null, "pmid": "24416042", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": "9564920;18237682;21545940;21828393;18157969;9187198;22781478;1554280;22286318;10343262;3578337;3402473;17126093;10086560;8205898;8717275;17954049;19026798;21463149;23569119;15073656;9922851;21403872;25850782;1898223;17629183;16244768;15275631;715813", "title": "Isolated left main coronary artery stenosis after thoracic radiation therapy: to operate or not to operate.", "title_normalized": "isolated left main coronary artery stenosis after thoracic radiation therapy to operate or not to operate" }

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ISOLATED LEFT MAIN CORONARY ARTERY STENOSIS AFTER THORACIC RADIATION THERAPY: TO OPERATE OR NOT TO OPERATE. CASE REPORTS IN MEDICINE. 2013;XX:XX", "literaturereference_normalized": "isolated left main coronary artery stenosis after thoracic radiation therapy to operate or not to operate", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171214", "receivedate": "20171214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14284006, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "A heavily pretreated patient with triple negative breast cancer distinguished by cutaneous metastases received p53MVA vaccine in combination with pembrolizumab. Her cutaneous metastases regressed and after 2 cycles of therapy, a skin biopsy showed a complete pathological response. Systemic response was confirmed with restaging CT and bone scans. Activation of p53-specific T cell responses and elevation of multiple immune response genes in peripheral blood correlated with the rapid clinical response which lasted for 6 months after the initiation of combined therapy.", "affiliations": "Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Research Operations, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Research Operations, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.;Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.", "authors": "Yuan|Yuan|Y|;Kos|Ferdynand J|FJ|;He|Ting-Fang|TF|;Yin|Hongwei H|HH|;Li|Mengsha|M|;Hardwick|Nicola|N|;Zurcher|Kathryn|K|;Schmolze|Daniel|D|;Lee|Peter|P|;Pillai|Raju K|RK|;Chung|Vincent|V|;Diamond|Don J|DJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/2162402X.2017.1363138", "fulltext": null, "fulltext_license": null, "issn_linking": "2162-4011", "issue": "6(12)", "journal": "Oncoimmunology", "keywords": "MVA; PD-1; T cell response; immunotherapy; p53; pembrolizumab; triple negative breast cancer; vaccine; vaccinia", "medline_ta": "Oncoimmunology", "mesh_terms": null, "nlm_unique_id": "101570526", "other_id": null, "pages": "e1363138", "pmc": null, "pmid": "29209571", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "28280247;27079802;20182602;22713868;23948975;25941580;25242720;23462680;24987057;22495314;16391808;27138582;23000897;17219151;10676655;21843052;27184417;28280249;24764583;28228704", "title": "Complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53MVA vaccine with pembrolizumab.", "title_normalized": "complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53mva vaccine with pembrolizumab" }

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COMPLETE REGRESSION OF CUTANEOUS METASTASES WITH SYSTEMIC IMMUNE RESPONSE IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER RECEIVING P53MVA VACCINE WITH PEMBROLIZUMAB. 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm recurrence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pathological fracture", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2015" } }, "primarysource": { "literaturereference": "YUAN Y, KOS FJ, HE TF, YIN HH, LI M, HARDWICK N ET AL.. COMPLETE REGRESSION OF CUTANEOUS METASTASES WITH SYSTEMIC IMMUNE RESPONSE IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER RECEIVING P53MVA VACCINE WITH PEMBROLIZUMAB. ONCOIMMUNOLOGY. 2017?6(12)", "literaturereference_normalized": "complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53mva vaccine with pembrolizumab", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180105", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14353848, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.", "affiliations": "Department of Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA, 94611, USA.;Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA.;Department of Orthopedic Surgery, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.;Department of Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA, 94611, USA. Joan.C.Lo@kp.org.", "authors": "Gu|K D|KD|;Ettinger|B|B|;Grimsrud|C D|CD|;Lo|J C|JC|http://orcid.org/0000-0002-7159-0648", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates", "country": "England", "delete": false, "doi": "10.1007/s00198-021-05948-w", "fulltext": null, "fulltext_license": null, "issn_linking": "0937-941X", "issue": "32(10)", "journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA", "keywords": "Atypical femur fracture; Bisphosphonate; Stress; Teriparatide", "medline_ta": "Osteoporos Int", "mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005269:Femur; D015775:Fractures, Stress; D006801:Humans", "nlm_unique_id": "9100105", "other_id": null, "pages": "2119-2123", "pmc": null, "pmid": "33914104", "pubdate": "2021-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy.", "title_normalized": "progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy" }

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PROGRESSION OF ATYPICAL FEMUR STRESS FRACTURE AFTER DISCONTINUATION OF BISPHOSPHONATE THERAPY.. 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CITRATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2000 IU PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atypical fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Wrist fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GU KD, ETTINGER B, GRIMSRUD CD, LO JC.. PROGRESSION OF ATYPICAL FEMUR STRESS FRACTURE AFTER DISCONTINUATION OF BISPHOSPHONATE THERAPY. OSTEOPOROSIS INTERNATIONAL. 2021?121 TO 122", "literaturereference_normalized": "progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210607", "receivedate": "20210526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19306220, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1922404", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ESTROGENS, CONJUGATED" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": ".45 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENOPAUSAL SYMPTOMS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".45", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CONJUGATED EQUINE ESTROGENS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076984", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70MG ONCE IN A WEEK, SINCE 9 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOPENIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM CITRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1800 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM CITRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MICROGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2000 IU (INTERNATIONAL UNIT) DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" } ], "patientagegroup": "6", "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rebound effect", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Wrist fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atypical fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atypical femur fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Osteoporotic fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GU KD, ETTINGER B, GRIMSRUD CD, LO JC. PROGRESSION OF ATYPICAL FEMUR STRESS FRACTURE AFTER DISCONTINUATION OF BISPHOSPHONATE THERAPY. OSTEOPOROS?INT 2021?:.", "literaturereference_normalized": "progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210617", "receivedate": "20210617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19433141, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nPulmonary arterial hypertension (PAH), is a rare manifestation of systemic lupus erythematosus (SLE), characterized by pulmonary arterial remodeling leading to right ventricular failure and death. To date, optimal management of SLE-associated PAH should be clarified, especially regarding the respective places of immunosuppressants and PAH vasodilator treatments.\n\n\nMETHODS\nWe report the case of a 48-year-old woman with SLE and secondary Sjogren syndrome, associated with severe PAH and lupus peritonitis with massive ascites, who showed a remarkable response, both for SLE flare and PAH, to a treatment combining immunosuppressants and pulmonary arterial vasodilator treatment.\n\n\nCONCLUSIONS\nThis observation highlights the interest of combining immunosuppressive therapy in SLE-PAH, whose modalities in association with PAH treatments should be clarified.", "affiliations": "Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Physiologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.", "authors": "Yucel|H|H|;Vollmer|O|O|;Canuet|M|M|;Enache|I|I|;Kessler|R|R|;Korganow|A S|AS|;Riou|M|M|https://orcid.org/0000-0001-6807-8582", "chemical_list": "D007166:Immunosuppressive Agents; D014665:Vasodilator Agents", "country": "England", "delete": false, "doi": "10.1177/0961203320976982", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "30(3)", "journal": "Lupus", "keywords": "Systemic lupus erythematosus; ascites; lupus peritonitis; pulmonary arterial hypertension", "medline_ta": "Lupus", "mesh_terms": "D001201:Ascites; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D000081029:Pulmonary Arterial Hypertension; D012859:Sjogren's Syndrome; D014665:Vasodilator Agents", "nlm_unique_id": "9204265", "other_id": null, "pages": "510-513", "pmc": null, "pmid": "33655792", "pubdate": "2021-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary Sjogren's syndrome.", "title_normalized": "severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary sjogren s syndrome" }

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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peritonitis lupus", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Yucel H.. Severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary Sjogren?s syndrome. 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"drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIFFU?K" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MICROGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROX" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peritonitis lupus", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 202001" } }, "primarysource": { "literaturereference": "YUCEL H.. SEVERE PULMONARY ARTERIAL HYPERTENSION AND MASSIVE ASCITES IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND SECONDARY SJOGREN?S SYNDROME.. LUPUS.. 2021?30 (3)::510?513.", "literaturereference_normalized": "severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary sjogren s syndrome", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210922", "receivedate": "20210717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19573411, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "BACKGROUND\nPiroxicam is a widely used anti-inflammatory drug. Most adverse reactions affect gastrointestinal system, liver and skin. Fixed drug eruption although very unusual, has also been described, but with cutaneous involvement exclusively. We present the case of a 49-year-old man who suffered three episodes of fixed drug eruption with cutaneous-mucosal involvement, even simulating an autoimmune disease, whenever he was treated with oral piroxicam.\n\n\nRESULTS\nHe was patch tested on normal skin with the GEIDC standard series and an NSAIDs series. He was patch tested on normal skin and on fixed eruption with piroxicam, meloxicam and tenoxicam (all of them 1 % pet). Oral challenge test was not performed due to the severity and reproducibility in previous reactions. Results showed a positive patch test to piroxicam (1 % pet) on fixed eruption, with negative results to the rest.\n\n\nCONCLUSIONS\nAdverse drug reactions may present a wide variability of clinical symptoms. In these situations an accurate clinical history is necessary. To our knowledge this is the 1st report of non-pigmenting fixed drug eruption with cutaneous-mucosal involvement due to piroxicam. Cross-reactivity between oxicams could not be demonstrated by patch test on fixed eruption.", "affiliations": "Allergy Unit, Internal Medicine Department, Hospital La Plana, Villarreal, Castellón, Spain.", "authors": "Montoro|J|J|;Díaz|M|M|;Genís|C|C|;Lozano|A|A|;Bertomeu|F|F|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D000077239:Meloxicam; C032801:tenoxicam", "country": "Singapore", "delete": false, "doi": "10.1016/s0301-0546(03)79165-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0301-0546", "issue": "31(1)", "journal": "Allergologia et immunopathologia", "keywords": null, "medline_ta": "Allergol Immunopathol (Madr)", "mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001528:Behcet Syndrome; D002081:Buttocks; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D006119:Groin; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D019226:Oral Ulcer; D010328:Patch Tests; D010409:Penile Diseases; D010894:Piroxicam; D012883:Skin Ulcer; D013843:Thiazines; D013844:Thiazoles", "nlm_unique_id": "0370073", "other_id": null, "pages": "53-5", "pmc": null, "pmid": "12573211", "pubdate": "2003", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Non-pigmenting cutaneous-mucosal fixed drug eruption due to piroxicam.", "title_normalized": "non pigmenting cutaneous mucosal fixed drug eruption due to piroxicam" }

[ { "companynumb": "ES-PFIZER INC-2021485200", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "018147", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHONDROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FELDENE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCLE SPASMS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SASULEN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "018147", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "DISPERSIBLE TABLET", "drugdosagetext": "UNK, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHONDROPATHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FELDENE FLASH" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fixed eruption", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MONTORO, J.. NON?PIGMENTING CUTANEOUS?MUCOSAL FIXED DRUG ERUPTION DUE TO PIROXICAM. ALLERGOLOGIA ET IMMUNOPATHOLOGIA. 2003?31 (1):53?55", "literaturereference_normalized": "non pigmenting cutaneous mucosal fixed drug eruption due to piroxicam", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210517", "receivedate": "20210517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19265419, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "Objective Heart failure is currently the most serious complication of muscular dystrophy. The transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. In damaged myocytes or cardiomyocytes, TRPV2 translocates to the cytoplasmic membrane and enhances Ca influx, triggering cell damage. Evidence suggests that the inhibition of TRPV2 may be a new therapeutic target in heart failure. We found that tranilast, which is widely used as an anti-allergic drug, inhibits TRPV2. A pilot study was conducted to assess the safety and efficacy of tranilast in muscular dystrophy patients with cardiomyopathy. Methods After obtaining informed consent, two muscular dystrophy patients with advanced heart failure took tranilast (300 mg/day) for three months. Blood tests, echocardiography, electrocardiography (ECG), Holter ECG, analyses of the TRPV2 expression in peripheral mononuclear cells, and circulating micro ribonucleic acid profiling were performed to assess the safety and efficacy of tranilast. Results The brain natriuretic peptide levels decreased after treatment. The expression of TRPV2 on the cytoplasmic membrane of peripheral mononuclear cells was enhanced before treatment and was decreased after treatment. Some heart-related micro ribonucleic acids (miR-208a-5p, miR-223-3p) were elevated and then decreased after treatment. Some adverse events, including the potentiation of warfarin, the worsening of renal dysfunction, an increased heart rate and premature ventricular contractions, were observed. Conclusion Tranilast can inhibit TRPV2 and can be effective for treating heart failure, even in patients with muscular dystrophy. Although careful attention is needed, the inhibition of TRPV2 can be a new treatment target for cardiomyopathy. A multi-center trial is planned.", "affiliations": "Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Japan.;Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan.", "authors": "Matsumura|Tsuyoshi|T|;Matsui|Misa|M|;Iwata|Yuko|Y|;Asakura|Masanori|M|;Saito|Toshio|T|;Fujimura|Harutoshi|H|;Sakoda|Saburo|S|", "chemical_list": "D002121:Calcium Channel Blockers; D062367:ortho-Aminobenzoates; C012293:tranilast", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8651-16", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2909338410.2169/internalmedicine.8651-16Original ArticleA Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy Matsumura Tsuyoshi 1Matsui Misa 1Iwata Yuko 2Asakura Masanori 3Saito Toshio 1Fujimura Harutoshi 1Sakoda Saburo 1\n1 Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan\n2 Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Japan\n3 Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, JapanCorrespondence to Dr.　Tsuyoshi Matsumura, tmatsumura-toneyama@umin.org\n\n1 11 2017 1 2 2018 57 3 311 318 3 12 2016 6 6 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Objective \nHeart failure is currently the most serious complication of muscular dystrophy. The transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. In damaged myocytes or cardiomyocytes, TRPV2 translocates to the cytoplasmic membrane and enhances Ca influx, triggering cell damage. Evidence suggests that the inhibition of TRPV2 may be a new therapeutic target in heart failure. We found that tranilast, which is widely used as an anti-allergic drug, inhibits TRPV2. A pilot study was conducted to assess the safety and efficacy of tranilast in muscular dystrophy patients with cardiomyopathy. \n\nMethods \nAfter obtaining informed consent, two muscular dystrophy patients with advanced heart failure took tranilast (300 mg/day) for three months. Blood tests, echocardiography, electrocardiography (ECG), Holter ECG, analyses of the TRPV2 expression in peripheral mononuclear cells, and circulating micro ribonucleic acid profiling were performed to assess the safety and efficacy of tranilast. \n\nResults \nThe brain natriuretic peptide levels decreased after treatment. The expression of TRPV2 on the cytoplasmic membrane of peripheral mononuclear cells was enhanced before treatment and was decreased after treatment. Some heart-related micro ribonucleic acids (miR-208a-5p, miR-223-3p) were elevated and then decreased after treatment. Some adverse events, including the potentiation of warfarin, the worsening of renal dysfunction, an increased heart rate and premature ventricular contractions, were observed. \n\nConclusion \nTranilast can inhibit TRPV2 and can be effective for treating heart failure, even in patients with muscular dystrophy. Although careful attention is needed, the inhibition of TRPV2 can be a new treatment target for cardiomyopathy. A multi-center trial is planned. \n\ncardiomyopathycardioprotective therapymuscular dystrophytranilasttransient receptor potential cation channelsubfamily Vmember 2 (TRPV2)\n==== Body\nIntroduction\nThe life expectancy of patients with muscular dystrophy, including those with Duchenne muscular dystrophy (DMD), has been dramatically improved by mechanical ventilation. Now, heart failure is the most important complication in muscular dystrophy (1). Although cardioprotective agents such as angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) and beta-blockers have shown some effects (2), the cardiac function does not fully recover under treatment with these drugs, and the situation remains unsatisfactory for both patients and physicians. Since it is difficult for muscular dystrophy patients to undergo surgical interventions such as ventriculoplasty, artificial heart implantation, and cardiac transplantation, the development of efficient pharmacological treatments is an urgent task.\n\nThe transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a stretch-sensitive Ca channel. It is normally localized in the intracellular membrane compartments but translocates to the cytoplasmic membrane in damaged myocytes or cardiomyocytes and enhances the influx of Ca, which triggers the cell damage process (3). The overexpression of TRPV2 on the cytoplasmic membrane is observed in the cardiac and skeletal muscle of mdx mice and BIO 14.6 hamsters, animal models of muscular dystrophy that contain mutations in dystrophin and δ-sarcoglycan, respectively (4). The overexpression of TRPV2 at the sarcolemma was also observed in the skeletal muscle and cardiomyocytes of muscular dystrophy patients (4, 5) and cardiomyocytes of dilated cardiomyopathy (DCM) patients (5). Transgenic mice with the cardiac-specific overexpression of TRPV2 develop DCM (4).\n\nThe inhibition of TRPV2 using mutant TRPV2 and Ca-handling agents blocked the abnormal intracellular Ca influx and ameliorated the muscle pathology and motor function in mdx mice and BIO14.6 hamsters (6-8). In addition, the overexpression of the NT domain of TRPV2 blocked the plasma membrane accumulation of TRPV2 and improved cardiomyopathy in various animal models of DCM (4C30 mice, DOX-induced DCM mice, J2N-k hamsters) (5). We developed a high-throughput screening method and detected some compounds showing the inhibition of TRPV2. Tranilast, which is already approved as an anti-allergic drug, is one such drug and was effective in BIO14.6 hamsters and J2N-k hamsters (5, 6).\n\nThese facts suggest that tranilast could be useful in muscular dystrophy patients. Thus, we performed a pilot study in which tranilast was used to treat two muscular dystrophy patients with advanced cardiomyopathy. In both patients, the serum level of brain natriuretic peptide (BNP) decreased after the initiation of tranilast therapy.\n\nMaterials and Methods\nThe study protocol\nThe aim of this pilot study was to evaluate the safety and efficacy of tranilast in the treatment of heart failure in patients with muscular dystrophy. In addition, since this was the first study of the use of tranilast in the treatment of heart failure in humans, we also gathered data to assess the pharmacological mechanisms. The effects of tranilast on cardiomyopathy in animal models were dose-dependent. Since there had been some clinical trials using tranilast (600 mg/day) (9-11), a dose escalation study, in which tranilast was started at a dose of 300 mg/day and gradually titrated up to 600 mg/day (unless there were adverse events), was initially considered. However, the pharmaceutical company recommended that dose escalation be avoided, since they had seen increased adverse effects, such as urocystitis-like symptoms (1-5%) and hepatic dysfunction (11-23%), at higher doses (9-11). In addition, the ethics review board prescribed the use of the approved dose (300 mg/day). Consequently, the study was designed as an open single-arm study of tranilast (300 mg/day) for three months.\n\nThe subjects were muscular dystrophy patients who were ＞20 years of age with severe cardiac dysfunction [left ventricular dimension in diastole (LVDd)＞50 mm, FS＜20%]. Patients with severe hepatic dysfunction, renal dysfunction, eosinophilia, leucopenia, or thrombocytopenia were excluded since urocystitis-like symptoms, hepatic dysfunction/jaundice, renal dysfunction, leucopenia, and thrombocythemia are listed as clinically significant adverse reactions (unknown frequency) in the interview form for tranilast.\n\nAfter providing their informed consent, the participants took tranilast (300 mg/day) for three months. In principle, the doses of drugs that affect the cardiac function, such as ACEIs/ARBs, beta blockers, diuretics, digitalis, inotropic agents, and antiarrhythmic agents, were fixed during the study period. However, the attending physicians could optimize them when they recognized the need based on the patient's physical condition and/or laboratory data. The dose of tranilast was also fixed. However, the attending physicians could also adjust it when they considered that adverse events had occurred in association with the administration of tranilast and that the adjustment of the tranilast dose was necessary.\n\nClinical assessments were performed before and at one and three months after the initiation of tranilast (Fig. 1). Even when tranilast was stopped, the clinical assessments were continued on the same schedule.\n\nFigure 1. The protocol of this pilot study.\n\nTo assess the effects, cardiac functional indices, including echocardiographic parameters (LVDd, FS) and natriuretic peptide levels (human atrial natriuretic peptide: hANP, BNP), and cardiomyocyte damage indices, such as cardiac troponin T (cTnT) and creatine kinase isoform (CK-MB), were examined. The plasma transforming growth factor-beta 1 (TGF-β1) levels were evaluated, the TRPV2 expression in peripheral mononuclear cells (MNCs) was analyzed, and circulating micro ribonucleic acid (miRNA) profiling was performed to assess the pharmacological mechanisms. For the analysis of the TRPV2 expression in MNCs and miRNA profiling, control samples were obtained from four healthy adult volunteers. The participants understood that they were being included as a control in this study and provided their informed consent.\n\nCardiac events (deterioration of heart failure requiring intravenous inotropic, antiarrhythmic, and/or diuretic agents, cardiac death, total death), subjective symptoms, and vital signs (blood pressure, pulse rate, percutaneous oxygen saturation) were monitored. The New York Heart Association (NYHA) classification was not suitable for these patients because they were bedridden and could not perform daily activities.\n\nTo assess the safety, Holter electrocardiography (ECG) [mean heart rate, total number of premature ventricular contractions (PVCs)], blood tests [WBCs, eosinophils (Eo), platelets (Plt)], blood chemistry [cystatin C (CysC), creatinine (Crn), blood urea nitrogen (BUN), uric acid (UA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), lactate dehydrogenase (LDH), total bilirubin (T.Bil), C-reactive protein (CRP), Na, K, Cl], the international normalized ratio (INR) of prothrombin time, and a urinalysis (urinary protein, urinary sugar, occult blood) were also performed.\n\nThe primary endpoints of this study were LVDd and FS. The secondary endpoints were BNP, cTnT, and cardiac events. In unstable patients, additional assessments were performed to see the detailed changes. With regard to treatment after the study, the plan was to stop tranilast and then provide the best available care. However, if tranilast seemed effective, the participants could choose to continue treatment.\n\nThe protocol of this study was in accordance with the Declaration of Helsinki and was approved by the ethics board of National Hospital Organization Toneyama National Hospital (No. 1441). The protocols for the analysis of the TRPV2 expression in MNCs and miRNA profiling were approved by the ethics board of the National Cerebral and Cardiovascular Center (M27-080-2).\n\nThe analysis of the TRPV2 expression in MNCs\nMNCs were isolated from blood samples gathered into ethylenediaminetetraacetic acid (EDTA)-Na using Lymphoprep™ (Axis-SHIELD PoC AS, Oslo, Norway), and were then centrifuged at 800×g for 30 minutes at room temperature.\n\nFor immunostaining, we used affinity-purified polyclonal anti-TRPV2 antibodies (4, 5) which were raised by immunizing rabbits with a glutathione S-transferase (GST) fusion protein containing aa634-756 of mouse TRPV2 protein. Isolated MNCs immobilized on glass slides were fixed with 4% paraformaldehyde for 15 minutes at room temperature, permeabilized with 0.1% Triton™ X-100 (Axis-SHIELD PoC AS), incubated with the antibody (1 : 100 dilution) overnight at 4℃, and then incubated for 30 minutes at room temperature with Alexa Fluor 488 goat anti-rabbit IgG (H+L) (1 : 500 dilution) (Invitrogen, Carlsbad, USA).\n\nImages of MNCs stained with TRPV2 antibodies were analyzed by investigators (who were blinded to the samples), by confocal laser scanning microscopy (FLUOVIEWTM FV1000, Olympus, Tokyo, Japan) mounted on an objective lens (Olympus), using the National Institute of Health Imaging software program. The fluorescence intensity was scanned along lines selected in the center of an MNC. The fluorescence intensity corresponding to the surface region was calculated by subtracting the intensity of the intracellular region from that of the total area. To summarize the data for the membrane localization of TRPV2, the number of MNCs with a strong fluorescence signal at the cell edge (at least three times higher than the average fluorescence in the internal region) was counted (total number of MNCs analyzed: 30-100). We repeated the experiments twice using another affinity purified TRPV2 antibody (anti-human TRPV2 antibody raised by immunizing rabbits with maltose binding protein fusion protein containing aa635-729 of human TRPV2).\n\nRNA extraction and miRNA profiling\nPlasma samples were collected from EDTA-Na blood samples by centrifugation at 1,500×g and stored at -80°C. RNA was extracted from the plasma samples using the 3D-GeneⓇ RNA extraction reagent from a liquid sample kit (TORAY, Tokyo, Japan), according to the manufacturer's instructions. The extracted total RNA was labeled with the 3D-GeneⓇ miRNA labeling kit (TORAY). Labeled RNAs were hybridized onto 3D-GeneⓇ Human miRNA Oligo chips (TORAY) (12). The annotation and oligonucleotide sequences of the probes conformed to the miRBase miRNA database (http://www.mirbase.org/). After careful washing, the fluorescence signals were scanned with a 3D-GeneⓇ Scanner (TORAY) and were analyzed using the 3D-GeneⓇ Extraction software program (TORAY).\n\nThe raw data of each spot were normalized by substitution with the mean intensity of the background signal (determined by the signal intensities of all of the blank spots' and 95% confidence intervals). The measurements of spots with signal intensities that were greater than two standard deviations of the background signal intensity were considered to be valid. The relative expression level of a given miRNA was calculated by comparing the signal intensities of the valid spots throughout the microarray experiments. The normalized data were globally normalized per array, such that the median signal intensity was adjusted to 25.\n\nPatients\nTwo muscular dystrophy patients with severe cardiac dysfunction, who agreed with the aims and protocol of this study and wished to participate, were included in the present study.\n\nThe first case (Patient 1) was a 45-year-old man with Becker muscular dystrophy (BMD). He had a deletion of exons 3 and 4 in the dystrophin gene, which was detected by multiple ligation-dependent prove amplification (MLPA). He was non-ambulatory but could sit without any support. He had developed cardiac dysfunction and had started ACEI therapy 20 years previously and beta blocker therapy 11 years previously. He was resuscitated from cardiopulmonary arrest due to ventricular tachycardia (VT) and underwent the implantation of a cardioversion-defibrillation and biventricular pacing device 6 years previously. He was then admitted to our hospital due to an exacerbation of heart failure. A stable condition was barely maintained with the best available care, which included ACEI, a beta blocker, a phosphodiesterase 3 inhibitor (PDE3I), diuretics, antiarrhythmic agents, warfarin, and night-time non-invasive ventilation (NIV). However, at the beginning of this study, he still had severe cardiac dysfunction [left ventricular dilated dimension (LVDd), 65 mm; fractional shortening (FS), 4%; BNP, 144.2 pg/mL; cTnT 0.039 ng/mL].\n\nThe second case (Patient 2) was a 46-year-old man with unclassified muscular dystrophy. He was initially diagnosed with BMD based on his clinical appearance and the findings of a histological examination of a muscle biopsy specimen in another hospital over 30 years previously, but neither MLPA nor Sanger sequencing detected mutations in the dystrophin gene. He was non-ambulatory and was not able to sit alone. He developed respiratory failure and was started on NIV 19 years previously. Cardiac dysfunction was also detected, and ACEI therapy was started 5 years previously. Non-sustained VT was detected from one year previously. He was strongly advised to take a beta blocker and/or an antiarrhythmic agent but refused because he disliked being admitted to hospital and frequent hospital visits. He developed cardiopulmonary arrest due to an acute exacerbation of heart failure and was successfully resuscitated at his home three months previously and was transferred to our hospital. Although maximal therapy was given, including ACEI, PDE3I, diuretics, antiarrhythmic agents, and full-time tracheal mechanical ventilation, he presented with recurrent multi-organ infection, and still had severe cardiac dysfunction (LVDd 61 mm, FS 6%, BNP 164.3 pg/mL, cTnT 0.016 ng/mL).\n\nBoth patients understood the protocol of this study well and participated willingly; both provided their informed consent.\n\nResults\nThe clinical findings in Patient 1\nAfter the initiation of tranilast, the INR increased from 2.25 to 3.64 within one week. The dose of warfarin was adjusted from 1.5 mg/day to 1.0 mg/day according to the INR. He initially had no subjective cardiac symptoms. Although his total energy intake was not greatly changed, his meal portion increased just before starting tranilast because the number of meals supplied was reduced from five (200 Kcal×5/day) to three (350 Kcal×3/day) per day. In addition, his mother's health had deteriorated during the study period. He felt an increased pulse rate, and it was confirmed by Holter ECG (the mean heart rate increased from 75 bpm to 88 bpm at one month, and 87 bpm at three months). The PVC also increased from 2,891 beats/day to 7,712 beats/day at one month and 8,445 beats/day at three months. Nonetheless, the plasma BNP level decreased from 144.2 pg/mL to 119.7 pg/mL at one month and 99.8 pg/mL at three months. The serum UA level decreased from 8.5 mg/dL at the beginning to 4.5 mg/dL at both one and three months. No apparent changes were detected on echocardiography (LVDd, FS) or in cTnT, CysC, or the other indices. There were no other clinically relevant changes (Fig. 2A). All of the laboratory data are presented in Supplementary material 1.\n\nFigure 2. The clinical courses of both patients.\n\nThe clinical findings in Patient 2\nThe general condition of Patient 2 was serious, with recurrent multi-organ infection. Thus, there were fluctuations in various indices. Subjective symptoms, such as general fatigue were affected by his general condition, and it was difficult to evaluate the effects of tranilast. His BNP level was also unstable, but it decreased from 164.3 pg/mL to 102.6 pg/mL at one month and 64.5 pg/mL at seven weeks. Since his CysC level was elevated from 0.92 mg/L to 2.86 mg/L, it was thought that this might be an adverse effect of tranilast, and tranilast was stopped at 52 days. In addition, his water intake increased simultaneously because the BUN level was elevated (51.4 mg/dL), and dehydration was considered. The BNP then rapidly increased to 228.5 pg/mL at 66 days. After tranilast was restarted, the patient's BNP level decreased to 114.6 pg/mL at 79 days. The serum UA level was 9.8 mg/dL before treatment, 3.5 mg/dL at one month, and 5.5 mg/dL at three months. There were no apparent changes on echocardiography, Holter ECG, or cTnT (Fig. 2B). All of the laboratory data are presented in Supplementary material 2.\n\nThe analysis of the TRPV2 expression in MNCs\nIn the control samples, TRPV2 was diffusely expressed in the cytoplasm. In the samples of both patients, TRPV2 was preferentially present on the cytoplasmic membrane (Fig. 3A, arrows). After the initiation of tranilast, the ratios of MNCs expressing TRPV2 on the cytoplasmic membrane were decreased in both cases (Fig. 3A, B). A similar result was obtained by using another TRPV2 antibody.\n\nFigure 3. The analysis of the TRPV2 expression in the peripheral MNCs. A: The immunohistochemical expression of TRPV2 in the MNCs. B: The ratio of MNCs expressing TRPV2 on the cytoplasmic membrane. Open bar: controls, black bar: Patient 1, gray bar: Patient 2. pre: pre-treatment, 1mo: One month after starting tranilast, 3mo: Three months after starting tranilast\n\nThe miRNA expression profiles\nThe chipset examined over 2,000 miRNAs. However there were only three miRNAs (miR-208a-5p, miR-223-3p, miR-4443) that were expressed at a higher level in comparison to the control samples at the beginning of treatment; they decreased to the control levels at one month after the initiation of tranilast treatment, and were maintained at the same levels at three months after treatment in both patients (Fig. 4). The expression levels of miR-1-3p, miR-1-5p, miR-133a-3p, miR-133b-miRNAs that are known as muscle miRNAs (13)-were not elevated in these patients.\n\nFigure 4. The circulating miRNA profiles. Open bar: controls, black bar: Patient 1, gray bar: Patient 2. Pt1: patient 1, Pt2: patient 2, pre: pre-treatment, 1mo: One month after starting tranilast, 3mo: Three months after starting tranilast\n\nDiscussion\nHeart failure is a crucial prognostic factor in patients with muscular dystrophy, but there are various problems in the clinical assessment of the cardiac function. First, symptoms of heart failure in these patients are difficult to recognize. Their motor dysfunction is so severe that the cardiac load is extremely low. Heart failure progresses chronically and often concurrently with respiratory failure. Mechanical ventilation also greatly decreases the cardiac load. Physicians familiar with muscular dystrophy treat heart failure from the early asymptomatic stage. Consequently, few patients complain of the symptoms of heart failure, even in the advanced stage. Thus, it is difficult to assess the effects of treatment based on the subjective symptoms.\n\nSecond, there are many limitations in the evaluation of the cardiac function. Magnetic resonance imaging is impossible for many patients because of severe deformities or the need for mechanical ventilation. Echocardiography is also difficult in some patients due to narrow echo windows because of the patients' thoracic deformities. BNP frequently remains low, even in the advanced stage of heart failure (14), and 100 pg/mL is known as a critical point for the prognosis (15). A previous study of beta blocker therapy showed improvements in cardiac events, but no obvious changes were detected in the BNP levels (2). Consequently, multiple markers and serial evaluations are needed to assess the cardiac function.\n\nBoth of the patients who participated in this pilot study had terminal-stage heart failure. Their cardiac dysfunction was quite severe, despite the provision of the best available treatment. Nonetheless, the BNP levels of both patients decreased after the initiation of tranilast. Notably, in Patient 2, the BNP rapidly increased when he stopped tranilast, and it then decreased after it was restarted. Although the echocardiographic findings showed no obvious changes, these findings suggest that tranilast has beneficial effects on cardiomyopathy in muscular dystrophy patients.\n\nSeveral assessments of the pharmacological mechanism also supported the efficacy of tranilast. The first assessment was the analysis of the TRPV2 expression. Assessments of the TRPV2 expression in cardiomyocytes before and after treatment are ideal but impractical in human patients. Instead, the TRPV2 expression in peripheral MNCs was analyzed. TRPV2 was preferentially expressed on the cytoplasmic membrane of the peripheral MNCs in both patients. After starting tranilast, the ratio of MNCs expressing TRPV2 on the cytoplasmic membrane decreased to control levels. These data suggest that tranilast can actually inhibit TRPV2, even in humans.\n\nThe second assessment was the analysis of the expression of circulating miRNAs. This study showed the elevation of the miR-208a-5p, miR-223-3p, and miR-4443 expression before treatment, with decreased to control levels in both patients after the initiation of tranilast treatment. Among these miRNAs, miR-208a-5p is known to be a regulator of cardiac hypertrophy (16), and its inhibition is reported to improve heart failure (17). In addition, miR-233-3p is known as a marker of heart disease (18, 19). Although there were no changes in the cTnT level, these findings implied that tranilast can ameliorate cardiac damage. These findings not only supported the effects of tranilast, but also suggested that these assessments can be biomarkers in TRPV2 inhibition therapy.\n\nIt should be noted that the expression levels of miR-1s and miR-133s were not elevated in these patients. Although these miRNAs have been reported to be elevated in patients with muscular dystrophy (13), the present results seemed natural because both patients were advanced cases with severe muscle atrophy.\n\nWith respect to safety, several adverse events occurred during the study period. It is well known that tranilast, which is mainly metabolized by CYP2C9, has synergistic effects with warfarin. Patient 1, who took warfarin, showed an elevated INR and his dose of warfarin required adjustment. Renal dysfunction is also a known adverse effect of tranilast. Based on the interview form, Crn elevation was found in 0.004% of patients who received the approved dose and 9.5% of the patients who received a higher dose (10). In the present study, Patient 2 showed cystatin C elevation. We suspected that dehydration and recurrent infection might also have affected the renal function, and his water intake was increased, but the value remained high. Thus, there was a high possibility that tranilast impaired the renal function. Since renal dysfunction is not rare in muscular dystrophy patients with heart failure (20), it can be a limiting factor. An increased heart rate and PVCs were observed in Patient 1. Tranilast is not known to cause such events. An increase in the food portions and/or mental stress might have been related to the patient's increased heart rate; however, an adverse effect of tranilast could not be ruled out. Although tranilast has been widely used in the general population, careful attention is needed when it is used in the treatment of patients with severe heart failure.\n\nThe results obtained from this pilot study suggest that the inhibition of TRPV2 might become a new therapeutic target for heart failure and myopathy. New options for the treatment of heart failure are of great clinical importance. We are planning multi-center clinical trials to clarify the safety and efficacy of tranilast.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis study was partly supported by a Health and Labour Sciences Research Grant for Comprehensive Research on Persons with Disabilities from Japan Agency for Medical Research and Development (15Adk0310043h0002) and an Intramural Research Grant (25-5, 26-6) for Neurological and Psychiatry Disorders of NCNP. The funders had no roles in the study design, data collection and analyses, decision to publish, or the preparation of the manuscript.\n\nSupplementary Materials\nSupplementary table 1 Laboratory data of Patient 1\n\nClick here for additional data file.\n\n Supplementary table 2 Laboratory data of Patient 2\n\nClick here for additional data file.\n\n Acknowledgement\nThe authors are grateful to Drs. Ryu Nagata and Hideki Ohta of the Japan Agency for Medical Research and Development for their kind advice on the circulating miRNA and metabolome analyses.\n==== Refs\n1. Matsumura T , Saito T , Fujimura H , Shinno S , Sakoda S \nA longitudinal cause-of-death analysis of patients with Duchenne muscular dystrophy . Rinsho Shinkeigaku \n51 : 743 -750 , 2011 (in Japanese, Abstract in English).22019865 \n2. Matsumura T , Tamura T , Kuru S , Kikuchi Y , Kawai M \nCarvedilol can prevent cardiac events in Duchenne muscular dystrophy . Intern Med \n49 : 1357 -1363 , 2010 .20647648 \n3. Kanzaki M , Zhang YQ , Mashima H , Shibata H , Kojima I \nTranslocation of a calcium-permeable cation channel induced by insulin-like growth factor-1 . Nat Cell Biol \n1 : 165 -170 , 1999 .10559903 \n4. Iwata Y , Katanosaka Y , Arai Y , Komamura K , Miyatake K , Shigekawa M \nA novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel . J Cell Biol \n161 : 957 -967 , 2003 .12796481 \n5. Iwata Y , Ohtake H , Suzuki O , Matsuda J , Komamura K , Wakabayashi S \nBlockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy . Cardiovasc Res \n99 : 760 -768 , 2013 .23786999 \n6. Iwata Y , Katanosaka Y , Shijun Z , et al \nProtective effects of Ca2+ handling drugs against abnormal Ca2+ homeostasis and cell damage in myopathic skeletal muscle cells . Biochem Pharmacol \n70 : 740 -751 , 2005 .16009351 \n7. Iwata Y , Katanosaka Y , Arai Y , Shigekawa M , Wakabayashi S \nDominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models . Hum Mol Genet \n18 : 824 -834 , 2009 .19050039 \n8. Zanou N , Iwata Y , Schakman O , Lebacq J , Wakabayashi S , Gailly P \nEssential role of TRPV2 ion channel in the sensitivity of dystrophic muscle to eccentric contractions . FEBS Lett \n583 : 3600 -3604 , 2009 .19840792 \n9. Kato K , Tamai H , Hayakawa H , et al \nClinical evaluation of tranilast on restenosis after percutaneous transluminal coronary angiopathy (PTCA) -a double-blind placebo-controlled comparative study- . Rinshoiyaku \n12 : 65 -85 , 1996 (in Japanese, Abstract in English).\n10. Itagane H , Haji K , Kodama K , et al \nEffects of tranilast on restenosis after percutaneous transluminal coronary angiopathy -a multi center phase III open trial- . Shinnyaku to Rinsho \n45 : 267 -280 , 1996 (in Japanese, Abstract in English).\n11. Takekoshi N , Kanemitsu S , Kitayama M , et al \nClinical evaluation of tranilast in the prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) -a phase III multicenter open trial- . Kiso to Rinsho \n30 : 593 -609 , 1996 (in Japanese, Abstract in English).\n12. Nagino K , Nomura O , Takii Y , et al \nUltrasensitive DNA chip: gene expression profile analysis without RNA amplification . J Biochem \n139 : 697 -703 , 2006 .16672270 \n13. Cacchiarelli D , Legnini I , Martone J , et al \nmiRNAs as serum biomarkers for Duchenne muscular dystrophy . EMBO Mol Med \n3 : 258 -265 , 2011 .21425469 \n14. Demachi J , Kagaya Y , Watanabe J , et al \nCharacteristics of the increase in plasma brain natriuretic peptide level in left ventricular systolic dysfunction, associated with muscular dystrophy in comparison with idopathic dilated cardiomyopathy . Neurmuscul Disord \n14 : 732 -739 , 2004 .\n15. Adachi K , Kawai H , Kimura C , et al \nEstimation of the prognosis of patients with Duchenne muscular dystrophy and cardiac failure on their plasma level of natriuretic peptide . Shinkeinaika 1998 \n49 : 532 -536 , 1998 (in Japanese, Abstract in English).\n16. Callis TE , Pandya K , Seok HY , et al \nMicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice . J Clin Invest \n119 : 2772 -2786 , 2009 .19726871 \n17. Montgomery RL , Hullinger TG , Semus HM , et al \nTherapeutic inhibition of miR-208a improves cardiac function and survival during heart failure . Circulation \n124 : 1537 -1547 , 2011 .21900086 \n18. Dickinson BA , Semus HM , Montgomery RL , et al \nPlasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure . Eur J Heart Fail \n15 : 650 -659 , 2013 .23388090 \n19. Barsanti C , Trivella MG , D'Aurizio R , et al \nDifferential regulation of microRNAs in end-stage failing hearts is associated with left ventricular assist device unloading . Biomed Res Int \n2015 (Epub ahead of print).\n20. Matsumura T , Saito T , Fujimura H , Sakoda S \nRenal dysfunction is a frequent complication in patients with advanced stage of Duchenne muscular dystrophy . Rinsho Shinkeigaku \n52 : 211 -217 , 2012 (in Japanese, Abstract in English).22531652\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(3)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "cardiomyopathy; cardioprotective therapy; member 2 (TRPV2); muscular dystrophy; subfamily V; tranilast; transient receptor potential cation channel", "medline_ta": "Intern Med", "mesh_terms": "D002121:Calcium Channel Blockers; D004334:Drug Administration Schedule; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D009136:Muscular Dystrophies; D010865:Pilot Projects; D062367:ortho-Aminobenzoates", "nlm_unique_id": "9204241", "other_id": null, "pages": "311-318", "pmc": null, "pmid": "29093384", "pubdate": "2018-02-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21900086;16672270;21425469;25710008;12796481;19050039;22019865;19726871;23388090;20647648;15482958;19840792;16009351;10559903;22531652;23786999", "title": "A Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy.", "title_normalized": "a pilot study of tranilast for cardiomyopathy of muscular dystrophy" }

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A PILOT STUDY OF TRANILAST FOR CARDIOMYOPATHY OF MUSCULAR DYSTROPHY. 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"reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUMURA T, MATSUI M, IWATA Y, ASAKURA M, SAITO T, FUJIMURA H, ET AL. A PILOT STUDY OF TRANILAST FOR CARDIOMYOPATHY OF MUSCULAR DYSTROPHY. INTERN MED. 2018?57(3):311?318", "literaturereference_normalized": "a pilot study of tranilast for cardiomyopathy of muscular dystrophy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180828", "receivedate": "20180817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15287049, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-TEVA-2018-JP-945725", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRANILAST" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM DAILY; FOR 3 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BECKER^S MUSCULAR DYSTROPHY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRANILAST" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Heart rate increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ventricular extrasystoles", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUMURA T, MATSUI M, IWATA Y, ASAKURA M, SAITO T, FUJIMURA H, ET AL. 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{ "abstract": "Düzova A, Gülhan B, Topaloğlu R, Özaltın F, Cengiz AB, Yetimakman AF, Doğru D, Güçer Ş, Beşbaş N. BK virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with Schimke immune-osseous-dysplasia. Turk J Pediatr 2019; 61: 111-116. Patients with juvenile onset Schimke immune-osseous-dysplasia (SIOD) have less severe symptoms and can survive in the second and third decade of life. We present an 18 year-old adolescent with juvenile onset SIOD who was diagnosed after renal transplantation and developed BK virus associated nephropathy (BKVAN) and severe pneumonia during follow-up. The patient developed nephrotic syndrome, unresponsive to immunosuppressives, at the age of 8 years. He had a history of meningitis, short stature, microcephaly, prominent ears, and bilateral cryptorchidism. A renal transplantation was performed at the age of 15 years. During follow-up, he suffered from leucopenia, urinary tract infections, herpes labialis, and candida esophagitis. Sanger sequencing of SMARCAL1 revealed a missense mutation on exon 11 (R586W). A renal biopsy performed after a sharp increase in serum creatinine (without significant viremia) revealed BKVAN which responded to sirolimus monotherapy and cidofovir. Three months later, he suffered from productive cough and dyspnea with diffuse ground glass pulmonary infiltrates. His clinical situation deteriorated and non-invasive mechanical ventilation was started. Cidofovir (2 mg/kg) was re-started weekly for a possible BKV pneumonia with intravenous immunoglobulin. After 5 doses of cidofovir and intense antibiotic regime, his dyspnea resolved with stable graft functions. In our case; BKVAN, which developed without significant viremia, and possibly associated pneumonia were treated successfully with cidofovir and sirolimus monotherapy.", "affiliations": "Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Intensive Care, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Pulmonary Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatric and Perinatal Pathology Research, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatrics Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.", "authors": "Düzova|Ali|A|;Gülhan|Bora|B|;Topaloğlu|Rezan|R|;Özaltın|Fatih|F|;Cengiz|Ali Bülent|AB|;Yetimakman|Ayşe Filiz|AF|;Doğru|Deniz|D|;Güçer|Şafak|Ş|;Beşbaş|Nesrin|N|", "chemical_list": "C412482:SMARCAL1 protein, human; D004265:DNA Helicases", "country": "Turkey", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-4301", "issue": "61(1)", "journal": "The Turkish journal of pediatrics", "keywords": "BK virus associated nephropathy; Schimke immuneosseous- dysplasia; kidney transplant; pneumonia; sirolimus", "medline_ta": "Turk J Pediatr", "mesh_terms": "D000293:Adolescent; D001161:Arteriosclerosis; D001739:BK Virus; D004265:DNA Helicases; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias; D011024:Pneumonia, Viral; D027601:Polyomavirus Infections; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism; D066027:Transplant Recipients", "nlm_unique_id": "0417505", "other_id": null, "pages": "111-116", "pmc": null, "pmid": "31559731", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": null, "title": "BK virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with Schimke immuneosseous- dysplasia.", "title_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia" }

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"patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A ET AL.. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA.. TURKISH JOURNAL OF PEDIATRICS. 2019?61(1):111-6", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191121", "receivedate": "20191121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17060417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-ACCORD-162396", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PREDNISOLONE DOSAGE WAS INCREASED", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DECREASED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA L, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURKISH JOURNAL OF PEDIATRICS. 2019?61(1):111-116.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191130", "receivedate": "20191130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17094769, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-TEVA-2019-TR-1146553", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viral test positive", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral herpes", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia viral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cytomegalovirus test positive", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA L, GULHAN B, TOPALOGLU R, OZALTIN F, BULENT CENGIZ A, FILIZ YETIMAKMAN A, ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURK-J-PEDIATR 2019?61(1):111-116.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200106", "receivedate": "20191205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17118180, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "TR-PBT-000012", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "05203", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEICOPLANIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, 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"drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL CANDIDIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "05203", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN (CYCLOSPORIN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL CANDIDIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": "3", "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, CENGIZ AB, YETIMAKMAN AF ET AL. BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS- DYSPLASIA. TURK J PEDIATR. 2019?61(1):111-116. DOI: 10.24953/TURKJPED.2019.01.018.", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20191014", "receivedate": "20191014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16913433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "TR-PBT-000041", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "829160000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "3", "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oral herpes", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oesophageal candidiasis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mouth ulceration", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kidney transplant rejection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUZOVA A, GULHAN B, TOPALOGLU R, OZALTIN F, CENGIZ AB, YETIMAKMAN AF, ET. AL BK VIRUS ASSOCIATED NEPHROPATHY AND SEVERE PNEUMONIA IN A KIDNEY TRANSPLANTED ADOLESCENT WITH SCHIMKE IMMUNEOSSEOUS-DYSPLASIA. TURKISH JOURNAL OF PEDIATRICS. 2019 JAN 1?61(1).", "literaturereference_normalized": "bk virus associated nephropathy and severe pneumonia in a kidney transplanted adolescent with schimke immuneosseous dysplasia", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200513", "receivedate": "20200513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17779233, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "OBJECTIVE\nAdamantinomas are primary, low-grade malignant tumors of the bone that have metastatic potential to the lungs, lymph nodes, and other regions. The rarity of this disease and its nonspecific symptoms complicate diagnosis.\n\n\nMETHODS\nRecords for 20 patients who underwent treatment for adamantinoma from 1975 to 2018 were reviewed for demographic, clinical, and pathological data, treatment details, postoperative complications, and outcomes.\n\n\nRESULTS\nPatients presented at a median age of 22 years (1-79 years): 14 patients had a localized primary tumor, three presented with local recurrence, and three with metastatic disease. Median tumor size was 5.7 cm (0.5-15.5 cm). Wide excision was performed primarily in 15 cases; the remaining five patients underwent intralesional curettage. At a median follow-up of 7.3 years, 14 patients had no evidence of disease; two patients were alive with disease, and four patients died from the disease. Local recurrence and distant metastasis occurred at a median of 11.4 years (6 month-19 years) and 15.8 years (4 month-23 years) after diagnosis.\n\n\nCONCLUSIONS\nAdequate histopathological diagnosis is crucial to avoid misdiagnosis of this rare tumor. Local and distant recuAbs_Para_meprrence can occur more than 20 years after the initial diagnosis. Life-long follow-up with clinical examination and imaging is required.", "affiliations": "Sloan Kettering Institute, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.", "authors": "Schwarzkopf|Eugenia|E|http://orcid.org/0000-0002-0305-5686;Tavarez|Yoely|Y|;Healey|John H|JH|http://orcid.org/0000-0002-0802-1186;Hameed|Meera|M|;Prince|Daniel E|DE|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/jso.25950", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-4790", "issue": "122(2)", "journal": "Journal of surgical oncology", "keywords": "adamantinoma; bone-tumor; low-grade; osteofibrous dysplasia", "medline_ta": "J Surg Oncol", "mesh_terms": "D050398:Adamantinoma; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011183:Postoperative Complications; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "0222643", "other_id": null, "pages": "273-282", "pmc": null, "pmid": "32334443", "pubdate": "2020-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1391818;18279517;2020866;3201280;30332521;1112840;16550582;27745864;21983933;3312206;29770232;2743266;8425352;18521211;9808442;16636523;7929496;19048403;27630780;2017924;3514033;17375547;3952546;10954102;2161603;7511328;6181697;6207973;16906392;12679847;17939469;28249983;7567680;31021853", "title": "Adamantinomatous tumors: Long-term follow-up study of 20 patients treated at a single institution.", "title_normalized": "adamantinomatous tumors long term follow up study of 20 patients treated at a single institution" }

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ADAMANTINOMATOUS TUMORS: LONG?TERM FOLLOW?UP STUDY OF 20 PATIENTS TREATED AT A SINGLE INSTITUTION. JOURNAL OF SURGICAL ONCOLOGY. 2020 APR 13?122(2):273?282. DOI:10.1002/JSO.25950", "literaturereference_normalized": "adamantinomatous tumors long term follow up study of 20 patients treated at a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200915", "receivedate": "20200915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18265646, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Cocoon abdomen is a rare condition in which abdominal structures are surrounded by thick encapsulating peritoneum resulting in dense adhesions. Liver transplant is a high risk surgery with an already increased risk of massive blood loss due to the pre-existing coagulopathy and portal hypertension. Presence of cocoon abdomen with severe dense adhesions can either lead to difficult hepatectomy with massive intra-operative blood loss or failure to proceed with the surgery. This becomes even more important in live donor liver transplantation where it may not be possible to abandon the surgery once the donor liver resection is started. Thus keeping a high suspicion of cocoon abdomen in patients with previous history of kochs abdomen and on long term beta blocker therapy is of utmost importance and this can decrease the morbidity and mortality associated with this condition. A 41 year old male known case of chronic liver disease was posted for live donor liver transplantation. After opening the abdomen thick dense adhesions were found around the intestines and the liver. Due to the dense adhesions surgical team was in dilemma whether to proceed further for the surgery or not. Intra-operatively patient had a blood loss of 12.5 litre. Despite massive transfusion the postoperative course went uneventful and the patient was extubated on 2nd post-operative day. He was shifted out of Intensive care unit on the 6th post-operative day. Cocoon abdomen should be suspected in a chronic liver disease patient with previous history of tuberculosis or on long term beta blocker therapy. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly shows that such types of patients can be taken up for the live donor liver transplantation surgery with a precaution to start donor hepatectomy only after surgeon has assessed the difficulty status of recipient hepatectomy.", "affiliations": "Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of HPB and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India.", "authors": "Garg|Neha|N|;Sindwani|Gaurav|G|;Arora|Mahesh Kumar|MK|;Pamecha|Vinyendra|V|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/sja.SJA_655_18", "fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-13-7510.4103/sja.SJA_655_18Case ReportLiving donor liver transplantation in a patient with cocoon abdomen – Anesthesia concerns! Garg Neha Sindwani Gaurav Arora Mahesh Kumar Pamecha Vinyendra 1Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi, India1 Department of HPB and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, IndiaAddress for correspondence: Dr. Gaurav Sindwani, Department of Anesthesia, Institute of Liver and Biliary Sciences, New Delhi - 110 070, India. E-mail: drsindwani25@gmail.comJan-Mar 2019 13 1 75 77 Copyright: © 2018 Saudi Journal of Anesthesia2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Cocoon abdomen is a rare condition in which abdominal structures are surrounded by thick encapsulating peritoneum resulting in dense adhesions. Liver transplant is a high risk surgery with an already increased risk of massive blood loss due to the pre-existing coagulopathy and portal hypertension. Presence of cocoon abdomen with severe dense adhesions can either lead to difficult hepatectomy with massive intra-operative blood loss or failure to proceed with the surgery. This becomes even more important in live donor liver transplantation where it may not be possible to abandon the surgery once the donor liver resection is started. Thus keeping a high suspicion of cocoon abdomen in patients with previous history of kochs abdomen and on long term beta blocker therapy is of utmost importance and this can decrease the morbidity and mortality associated with this condition. A 41 year old male known case of chronic liver disease was posted for live donor liver transplantation. After opening the abdomen thick dense adhesions were found around the intestines and the liver. Due to the dense adhesions surgical team was in dilemma whether to proceed further for the surgery or not. Intra-operatively patient had a blood loss of 12.5 litre. Despite massive transfusion the postoperative course went uneventful and the patient was extubated on 2nd post-operative day. He was shifted out of Intensive care unit on the 6th post-operative day. Cocoon abdomen should be suspected in a chronic liver disease patient with previous history of tuberculosis or on long term beta blocker therapy. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly shows that such types of patients can be taken up for the live donor liver transplantation surgery with a precaution to start donor hepatectomy only after surgeon has assessed the difficulty status of recipient hepatectomy.\n\nCocoon abdomenliving donorliver transplantation\n==== Body\nIntroduction\nCocoon abdomen is a rare condition characterized by thick peritoneum encapsulating the abdominal structures with adhesions.[1] It is also called as sclerosing encapsulating peritonitis. In most cases, it is diagnosed incidentally on laparotomy.[2] It usually presents clinically as acute or subacute small bowel obstruction.[3] Liver transplantation is a major surgery which usually requires multiple transfusions. There are various risk factors predisposing to blood loss such as history of previous abdominal surgery, presence of coagulopathy, presence of multiple collaterals, massive fluid resuscitation, hypothermia, and hypocalcemia. The presence of cocoon abdomen results in multiple adhesions. Moreover, with an increase in the chronicity of liver disease, the number of collaterals increases, which further infiltrates the adhesions present in cocoon abdomen. This causes further increase in blood loss in an already challenging surgery like liver transplantation and can pose a great challenge for an anesthetist. As per our literature search, the presence of cocoon abdomen also involving liver hilum leading to massive transfusion in a patient undergoing liver transplantation has not been reported. Hence, we present a case of a 41-year-old male patient with history of pulmonary tuberculosis for liver transplantation, incidentally diagnosed to have cocoon abdomen intraoperatively, leading to massive transfusion and dilemma whether to proceed further for the surgery.\n\nCase\nA 41-year-old male, weighing 76 kg, diagnosed with ethanol-related chronic liver disease with treated pulmonary tuberculosis was posted for living donor liver transplantation. He had history of pulmonary tuberculosis 6 months ago. The patient also had a history of ascites for which he was on tablet furosemide 80 mg/day and tablet metoprolol 25 mg. He had an Model for End stage Liver Disease (MELD) score of 30. Chest X-ray showed mild pleural effusion of the right side. Bubble contrast ECHO showed moderate shunting with room air PAO2 of 61 mmHg. On the day of the surgery, the patient was taken inside the operation theater. All standard American Society of Anaesthesiologists (ASA) monitors were attached. An 18-G intravenous cannula was secured in the left upper limb. General anesthesia was induced with inj. propofol 100 mg i.v., inj. fentanyl 100 μg i.v., and inj. rocuronium 100 mg i.v. Trachea was intubated with 8.5 Endotracheal Tube (ETT) and the patient was put on mechanical ventilation. Ultrasound-guided one 8.5-F four-lumen central line and one 9-F triple-lumen advanced vascular access sheath were secured in the right internal jugular vein. Two 20-G arterial cannula were secured, one each in radial artery. Fluid warmer, forced air warmer, and heating mattress were used to maintain normothermia in the patient. Anesthesia was maintained with oxygen and air (50:50), isoflurane, 1.5 μg/kg/h fentanyl infusion, and 0.5 mg/kg/hatracurium infusion. After opening the abdomen, dense adhesions with encapsulation of liver and bowel were found [Figure 1]. Along with this, multiple collaterals in hepatoduodenal ligament, perigastric region, pericholedochal, peri-gall bladder, and perimesentric were also present. This resulted in blood loss of 12.5 L in the dissection phase which was replaced with transfusion of 35 units of Packed Red Blood Cells (PRBCs), 15 units of cryoprecipitate, 15 units of Fresh Frozen Plasma (FFP), and 3 single-donor platelet concentrate; 24 L of plasmalyte and 2.25 L of albumin were also given. Noradrenaline and vasopressin were titrated intraoperatively to maintain a minimum mean arterial pressure of 60 mmHg. Warm ischemia time was 29 min, and the cold ischemia time was 1 h 36 min. The rest of the surgery went uneventful with mild post-reperfusion syndrome which was managed with 400 μg bolus of phenylephrine. The patient was shifted to the intensive care unit for elective mechanical ventilation with vasopressor support of noradrenaline 8 μg/min and vasopressin 1 unit/h. The liver functions started improving in the immediate postoperative period indicated by decreasing lactate levels, prothrombin time, International Normalized Ratio (INR), bilirubin, Aspartate Transaminase (AST), and (ALT) Alanine transaminases levels with good portal vein flow and hepatic artery flow on Doppler. The patient was successfully extubated on the second postoperative day despite massive transfusion and shifted out of the intensive care unit on the sixth postoperative day.\n\nFigure 1 Cocoon abdomen involving whole of the intestines with the liver graft in situ\n\n\nDiscussion\nCocoon abdomen is a rare condition in which thick fibrotic peritoneum covers the bowel along with adhesions. It is mostly found in females. It is of two types, primary and secondary. Primary is more common and is found in young females, proposed to arise from retrograde menstruation or primary transvaginal peritonitis. Secondary is due to B adrenergic blockers, abdominal tuberculosis, chronic ambulatory peritoneal dialysis, and liver cirrhosis after peritoneal venous shunt.[45]\n\nPreoperative diagnosis is difficult. Clinically, patients present with recurrent intestinal obstruction. Radiologic findings may help in suspected cases. Plain radiograph and oral contrast show a compact mass of bowel with delayed or absent passage of contrast. Ultrasound shows a tightly bound mass of bowel surrounded by a rim of echo poor tissue. Similarly, computed tomography scan can show a circumscribed cluster of small bowel loops.[67] Unfortunately, our patient did not have any of these findings preoperatively which could have lead to preoperative diagnosis of Sclerosing Encapsulating Peritonitis (SEP).\n\nOur patient had ethanol-related chronic liver disease with a previously diagnosed pulmonary tuberculosis which may have been attributed to SEP. The mechanism by which pulmonary tuberculosis can spread to abdomen includes ingestion of infected sputum, through lymphatic channels or through blood vessels. Thus, a high degree of suspicion for abdominal tuberculosis must be kept in mind for patients with pulmonary kochs presenting for liver transplant, and attempts for appropriate diagnosis for cocoon abdomen must be made preoperatively.\n\nOther etiology which might have caused SEP in our patient was the long-term use of metoprolol. Beta blockers which can be associated with the SEP are propanolol, timolol, metoprolol, and atenolol. The mechanism by which beta blockers causes SEP includes enhanced collagen production or an allergic reaction to the drug.[8]\n\nCirrhosis results in portal hypertension which leads to the development of collaterals around the liver. In cocoon abdomen, these small collaterals infiltrate the fibrotic tissue which can result in massive blood loss during the surgery. Therefore, probably our patient bled massively despite normal thromboelastography. Preoperative diagnosis and appropriate preparation for cocoon abdomen can help improve the postoperative morbidity and mortality in such patients.\n\nCocoon abdomen should be suspected in a patient with chronic liver disease with previous history of tuberculosis of any part of the body. Proper preparation before surgery can decrease the morbidity and mortality associated with this major surgery. Our case report clearly showed that such types of patients can be taken up for live donor liver transplantation surgery with a precaution to start donor hepatectomy only after the surgeon has assessed the difficulty status of recipient hepatectomy.\n\nInformed consent\nWritten informed consent was obtained from the patient.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Rastogi R Abdominal cocoon secondary to tuberculosis Saudi JGastroenterol 2008 14 139 41 19568523 \n2 Wei B Wei HB Guo WP Zheng ZH Huang Y Hu BG Diagnosis andtreatmentofabdominal cocoon: A report of 24 cases Am J Surg 2009 198 348 53 19217609 \n3 Singh B Gupta S Abdominal cocoon: A case series Int J Surg 2013 11 325 8 23459185 \n4 Debi U Ravisankar V Prasad KK Abdominal tuberculosis of the gastrointestinal tract: Revisited World J Gastroenterol 2014 20 14831 40 25356043 \n5 Lin CH Yu JC Chen TW Chan DC Chen CJ Hsieh CB Sclerosing encapsulatingperitonitis in a liver transplant patient: A case report World J Gastroenterol 2005 11 5412 3 16149160 \n6 Zaslavsky J Mulugeta-Gordon L Vasko I Presenza T Scattergood E Meislich D Tuberculous peritonitis in children: Two case reports highlighting the important role of imaging Radiol Case Rep 2018 13 862 6 30174770 \n7 Da Rocha EL Pedrassa BC Bormann RL Abdominal tuberculosis: A radiological review with emphasis on computed tomography and magnetic resonance imaging findings Radiol Bras 2015 48 181 91 26185345 \n8 Noh SH Ye BD So H Kim YS Suh DJ Yoon SN Sclerosing encapsulating peritonitis in a long-term propranolol user Intest Res 2016 14 375 8 27799890\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": null, "issue": "13(1)", "journal": "Saudi journal of anaesthesia", "keywords": "Cocoon abdomen; liver transplantation; living donor", "medline_ta": "Saudi J Anaesth", "mesh_terms": null, "nlm_unique_id": "101500601", "other_id": null, "pages": "75-77", "pmc": null, "pmid": "30692895", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "16149160;19217609;19568523;23459185;25356043;26185345;27799890;30174770", "title": "Living donor liver transplantation in a patient with cocoon abdomen - Anesthesia concerns!", "title_normalized": "living donor liver transplantation in a patient with cocoon abdomen anesthesia concerns" }

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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS. 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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. 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LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. 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"MAINTENANCE OF ANAESTHESIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "41", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "76", "reaction": [ { "reactionmeddrapt": "Encapsulating peritoneal sclerosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Collateral circulation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GARG N, SINDWANI G, ARORA MK, PAMECHA V. LIVING DONOR LIVER TRANSPLANTATION IN A PATIENT WITH COCOON ABDOMEN - ANESTHESIA CONCERNS!. SAUDI-J-ANAESTH 2019?13(1):75-77.", "literaturereference_normalized": "living donor liver transplantation in a patient with cocoon abdomen anesthesia concerns", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20190205", "receivedate": "20190205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15918343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" } ]

{ "abstract": "BACKGROUND\nACTH-independent Cushing's Syndrome (AICS) accounts for 15-20% of cases of Cushing's syndrome, with <1% due to abnormal receptors. Our aim is to study the presence of abnormal receptors in subjects diagnosed with AICS with nodular adrenal hyperplasia in a 14-year period (2002-2016), as well as its clinical-biological and evolutive characteristics.\n\n\nMETHODS\nA multicentre descriptive study of a 15-case series of AICS with nodular adrenal hyperplasia (study period: 2002-2016). In these cases, abnormal receptor screening was performed by means of stimulation tests, with a plasma cortisol increase of ≥ 25% from baseline being considered pathologic.\n\n\nRESULTS\nOf the 15 cases, 13 were female, with a mean age at diagnosis of 56.8 years. In 12 of the 15 cases studied, positivity was detected with stimulation tests, and, of them, 25% were positive for the meal test, 58.3% for posture walking test, 33.3% for desmopressin; 25% for terlipressin; 33.3% for GnRH; 25% for LH and 50% for metoclopramide. Regarding treatment, bilateral adrenalectomy was performed in 16.7% and unilateral adrenalectomy in 41.7%. The rest continue under observation with periodic follow-up (41.7%).\n\n\nCONCLUSIONS\nIn most of the cases studied with AICS and nodular adrenal hyperplasia (80%), an abnormal cortisol response is detected due to the presence of abnormal receptors. The test with the highest percentage of positivity was the postural walking test (58.3%).", "affiliations": "Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España.;Endocrinología y Nutrición, Hospital Marina Baixa, Villajoyosa (Alicante), España.;Endocrinología y Nutrición, Hospital de Gandía, Gandía (Valencia), España.;Endocrinología y Nutrición, Hospital de Dénia, Dénia (Alicante).;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España; Departamento de Medicina, Universidad de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). Electronic address: sergio.martinez@uv.es.;Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, España; Departamento de Medicina, Universidad de Valencia, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM).", "authors": "Ferri|Jordi|J|;Perelló|Eva|E|;Lorente|Rosario I|RI|;Argente|Carlos|C|;Rossetti|Paolo|P|;Pedro|Teresa|T|;Martinez-Hervas|Sergio|S|;Real|José T|JT|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.1016/j.endinu.2019.07.005", "fulltext": null, "fulltext_license": null, "issn_linking": "2530-0180", "issue": "67(4)", "journal": "Endocrinologia, diabetes y nutricion", "keywords": "Abnormal receptors; Cushing's syndrome; Hiperplasia suprarrenal nodular; Nodular adrenal hyperplasia; Receptor anómalo; Síndrome de Cushing", "medline_ta": "Endocrinol Diabetes Nutr (Engl Ed)", "mesh_terms": "D000311:Adrenal Glands; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "101717565", "other_id": null, "pages": "245-252", "pmc": null, "pmid": "31672533", "pubdate": "2020-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Study of abnormal adrenal receptors in subjects with ACTH-independent Cushing's syndrome and nodular adrenal hyperplasia.", "title_normalized": "study of abnormal adrenal receptors in subjects with acth independent cushing s syndrome and nodular adrenal hyperplasia" }

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E, LORENTE RI, ARGENTE C, ROSSETTI P, PEDRO T, ET AL. STUDY OF ABNORMAL ADRENAL RECEPTORS IN SUBJECTS WITH ACTH-INDEPENDENT CUSHING^S SYNDROME AND NODULAR ADRENAL HYPERPLASIA. ENDOCRINOLOGIA, DIABETES Y NUTRICION. 2019", "literaturereference_normalized": "study of abnormal adrenal receptors in subjects with acth independent cushing s syndrome and nodular adrenal hyperplasia", "qualification": null, "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200109", "receivedate": "20200109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17252608, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "ES-ABBVIE-19P-144-3193728-00", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "020011", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "3.75 MILLIGRAM, Q4WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PITUITARY-DEPENDENT CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUPRORELIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FERRI J, PERELLO E, LORENTE I, ET AL.. STUDY OF ABNORMAL ADRENAL RECEPTORS IN SUBJECTS WITH ACTH-INDEPENDENT CUSHING^S SYNDROME AND NODULAR ADRENAL HYPERPLASIA. ENDOCRINOLOGIA, DIABETES Y NUTRICION. 2019?.", "literaturereference_normalized": "study of abnormal adrenal receptors in subjects with acth independent cushing s syndrome and nodular adrenal hyperplasia", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "ES", "receiptdate": "20191217", "receivedate": "20191212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17146216, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in rapidly proliferating hematological malignancies and solid tumors prior to initiating cytotoxic therapy. We encountered a patient who originally presented with diffuse lymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities suggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed blastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney injury (AKI) and uric acid had improved with intravenous fluids and the initiation of allopurinol. However, after beginning chemotherapy, the patient developed a second AKI concerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not require renal replacement therapy. With the exception of case reports, there is limited evidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based guidelines are available to guide use of rasburicase, an uricase enzyme, before initiation of chemotherapy for certain malignancies when risk for TLS is considered high. Despite these guidelines, the role of rasburicase in preventing AKI remains controversial after inconclusive results in a meta-analysis. The causative relationship between uric acid and AKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by which uric acid may cause AKI without tubular obstruction related to acute hyperuricemic nephropathy. Further characterization of the role of uric acid in causing AKI in patients without tubular obstruction may identify new mechanisms of injury and offer insight into new treatment strategies.", "affiliations": "University of Florida, Gainesville, FL, USA.;University of Florida, Gainesville, FL, USA.", "authors": "Patel|Vishal|V|0000-0003-3759-9523;Case|Robert|R|", "chemical_list": "C469709:rasburicase; D014527:Uric Acid; D014503:Urate Oxidase", "country": "United States", "delete": false, "doi": "10.1177/2324709620944709", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620944709\n10.1177_2324709620944709\nCase Report\nSpontaneous Tumor Lysis Syndrome in Blastoid-Variant Mantle Cell Lymphoma:\nConsiderations for the General Internist\nhttps://orcid.org/0000-0003-3759-9523Patel Vishal MD1 Case Robert MD1 1 University of Florida, Gainesville, FL,\nUSA\nRobert Case, MD, Department of Internal Medicine,\nUniversity of Florida, 1600 SW Archer Road, Rm 4101, PO Box 100277, Gainesville, FL 32610,\nUSA. Email: Robert.Case@medicine.ufl.edu\n28 7 2020 \nJan-Dec 2020 \n8 232470962094470912 5 2020 15 6 2020 21 6 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in\nrapidly proliferating hematological malignancies and solid tumors prior to initiating\ncytotoxic therapy. We encountered a patient who originally presented with diffuse\nlymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities\nsuggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed\nblastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney\ninjury (AKI) and uric acid had improved with intravenous fluids and the initiation of\nallopurinol. However, after beginning chemotherapy, the patient developed a second AKI\nconcerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not\nrequire renal replacement therapy. With the exception of case reports, there is limited\nevidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based\nguidelines are available to guide use of rasburicase, an uricase enzyme, before initiation\nof chemotherapy for certain malignancies when risk for TLS is considered high. Despite\nthese guidelines, the role of rasburicase in preventing AKI remains controversial after\ninconclusive results in a meta-analysis. The causative relationship between uric acid and\nAKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by\nwhich uric acid may cause AKI without tubular obstruction related to acute hyperuricemic\nnephropathy. Further characterization of the role of uric acid in causing AKI in patients\nwithout tubular obstruction may identify new mechanisms of injury and offer insight into\nnew treatment strategies.\n\ntumor lysis syndromeuric acid nephropathyrasburicasecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nTumor lysis syndrome (TLS) is an oncologic emergency that often develops after initiating\nchemotherapy for hematologic malignancies and lymphomas with a high proliferation rate and\nsensitivity to chemotherapy.1,2 The elevated\nlevels of uric acid may lead to acute renal failure through multiple mechanisms including\nobstruction by precipitated uric acid crystals, cytokine release syndrome, and a decreased\nglomerular filtration rate.3-5 The Cairo-Bishop definition of TLS, which\ndescribes both laboratory and clinical TLS, was developed in 2004 to help clinicians\nidentify the diagnosis and grade its severity.6 Laboratory TLS is defined by multiple electrolyte abnormalities including\nhyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.7 Clinical TLS is determined by electrolyte changes plus a medical complication such as\nrenal failure, seizure, or cardiac arrhythmia.\n\nSpontaneous TLS (SPTLS) is a rare phenomenon that can develop in high-grade non-Hodgkin\nlymphomas and hematological malignancy due to rapid proliferation of malignant cells and auto-lysis.1 In this article, we describe a case that resulted in a diagnosis of blastoid-variant\nmantle cell lymphoma (MCL), with acute kidney injury (AKI) and a uric acid level of more\nthan 20 mg/dL at the time of presentation.\n\nCase Presentation\nA 62-year-old male presented to the emergency department with a 2-week history of\nprogressive shortness of breath with exertion. His medical history was relevant for\nβ-thalassemia minor, hypertension, and a 40-year pack history of tobacco use. He initially\nhad shortness of breath with a productive cough and was provided with a brief course of\nazithromycin by an outpatient physician. While he experienced relief from the cough, his\nexertional dyspnea continued to worsen, and he developed profound fatigue and night sweats.\nIn the days preceding hospital admission, he reported a noticeable reduction in his urine\noutput, which was associated with painless abdominal distention.\n\nHis initial blood counts showed leukocytosis to 21 000/mm3 with 10% lymphocytes\nand many atypical lymphocytes. He was also found to be thrombocytopenic to 42\n000/mm3. His initial creatinine was 3.37 mg/dL with blood urea nitrogen (BUN)\nof 44 mg/dL and initial potassium level of 5.8 mEq/L and phosphorus of 6.4 mg/dL. The\nurinalysis was largely normal with a pH of 5.0, specific gravity of 1.015, and no protein or\nreported crystals. Computed tomography scans of the chest, abdomen, and pelvis were obtained\nand revealed extensive lymphadenopathy both above and below the diaphragm. There was no\nevidence of ureteral obstruction on imaging. The largest lymph node was 1.9 cm in diameter,\nand the spleen was enlarged to 23 cm. Uric acid and lactate dehydrogenase (LDH) levels were\nthen obtained and revealed a uric acid level of 20 mg/dL and LDH of more than 1600 IU/L.\n\nThe AKI and acute presentation of dyspnea led to concern for sepsis at presentation. Broad\nspectrum antibiotics were started, but then discontinued when imaging ruled out\nconsolidations and when there were no infection found in the urinary tract. The patient\ndenied use of nonsteroidal anti-inflammatory drugs and was not exposed to contrast or other\nnephrotoxins prior to admission. The patient did report oliguria prior to admission and\nafter fluid resuscitation, his renal function gradually improved to 1.2 mg/dL from 3.37mg/dL\nin 8 days (Figure 1a). During this\nperiod of time, his uric acid decreased to 3.0 mg/dL from 21.7 mg/dL (Figure 1b). He was then transferred to the inpatient\noncology team while histology results from an axillary lymph node biopsy were pending.\n\nFigure 1. (a) Trend of creatinine during first 8 days of admission. (b) Trend in uric acid during\nfirst 8 days of admission.\n\nBoth the lymph node biopsy and peripheral flow cytometry revealed findings consistent with\nblastoid-variant MCL. The Ki67 of the specimen was greater than 90%. With concern that he\nwould develop an AKI on initiation of chemotherapy, he was preemptively started on\ncontinuous normal saline 200 mL/h and allopurinol at a dose of 300 mg 3 times daily. Due to\nthe improvement of his uric acid at the time, he did meet our hospital criteria to receive\nrasburicase prior to the initiation of chemotherapy. Chemotherapy with rituxumab and\nhyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone) was initiated. The\npatient remained on allopurinol while receiving chemotherapy.\n\nWithin 24 hours of beginning chemotherapy, the potassium, phosphate, and BUN levels rose\nsignificantly. The creatinine then began to increase with a peak of 2.69 mg/dL and a BUN of\n105 mg/dL. During the 48 hours immediately after starting chemotherapy, the potassium level\nincreased to more than 6.2 mEq/L and the phosphorus level to 12 mg/dL. The uric acid\nincreased minimally from 3 to 4 mg/dL. The patient continued to produce urine and responded\nto medical therapy primarily targeting hyperkalemia. Dialysis was not required, and as the\nchemotherapy cycle concluded, renal function started to improve after 3 days and creatinine\ntrended to a new baseline of 0.7 mg/dL.\n\nDiscussion\nFor patients with newly diagnosed lymphoma, risk for development of TLS is stratified from\nlow to high based on the anticipated aggressiveness of the malignancy and its anticipated\nsensitivity to chemotherapy.1,8 As it\npertains to the patient we have described, MCL of the blastoid variant subtype is considered\nhigh risk for TLS in cases where the LDH level is more than twice the upper limit of normal.9 On review, the presenting renal dysfunction, uric acid level of more than 20 mg/dL\nand hyperkalemia, with an ultimate diagnosis of an aggressive non-Hodgkin’s lymphoma, is\nclinically consistent with a diagnosis of spontaneous TLS. In our review of the literature,\nwe did not identify other examples of SPTLS with blastoid-variant lymphoma. SPTLS is a rare,\nbut accepted phenomenon that is thought to occur only in rapidly proliferating non-Hodgkin’s\nlymphomas and hematological malignancies.1 Since many cases of SPTLS can mimic other acute non-neoplastic diseases processes,\nthe diagnosis is challenging to confirm without malignant pathology. Additionally, consensus\nguidelines are not available to guide the general medicine clinician on how to specifically\nmanage the renal dysfunction associated with this condition.\n\nFor patients with SPTLS or standard TLS, uric acid elevation is thought to be the cause of\nAKI with most cases involving deposition of uric acid crystals in the nephron resulting in\nobstruction and increased tubular pressure.10,11 Increased tubular pressure directly\ndecreases filtration at the glomerulus. Ultimately, the inability to excrete water and\nelectrolytes may lead to uncontrollable electrolyte abnormalities and fluid overload, which\ncan subsequently result in an urgent requirement for dialysis. In our case, we initially\nassumed uric acid had caused the patient’s AKI by the mechanism described above; however,\nboth ultrasound and computed tomography imaging did not demonstrate evidence of\nnephrolithiasis. Furthermore, the gradual improvement of renal function and continued urine\noutput also left us questioning this classical mechanism of kidney injury. This led to our\nreview of alternative causes of AKI related to hyperuricemia.\n\nDuring the workup of our patient, urine eosinophils were absent, and urine microscopic\nanalysis did not reveal pathologic casts. Additionally, the patient had oliguria rather than\nanuria and did not require dialysis. For these reasons, the patient’s acute uric acid\nnephropathy and AKI were the result of elevated uric acid levels, but more likely due to\ncrystal independent mechanisms.4,10,12 Using animal models, uric\nacid has been shown to contribute to AKI by impairing renal autoregulation, the\nbioavailability of nitric oxide, and proximal tubular proliferation.4,13,14 Hahn et al10 reviewed this topic and described how elevated uric acid levels are associated with\nelevated levels of inflammatory mediators systemically and in the nephron. The release of\ncytokines including monocyte chemoattractant protein-1, tumor necrosis factor-α, and\nintercellular adhesion molecule 1 have been implicated in the nephrotoxicity that uric acid\npotentiates. In a rat model, mild hyperuricemia has also been described as causing a 50%\nreduction in glomerular filtration rate and renal blood flow.10,13 Uric acid impairs the bioavailability of\nnitric oxide, which results in further renal tissue ischemia through vasoconstriction.14 Considering these models for renal injury, future therapies may be developed to treat\ncrystal-independent renal dysfunction related to hyperuricemia.\n\nThe current standard for management of renal failure in TLS is based on minimizing tubular\nobstruction, diluting crystals, and preventing uric acid crystal formation by providing\nintravenous fluid and uric acid lowering therapy in the form of allopurinol or rasburicase.\nUse of allopurinol, as in our case, is beneficial in preventing uric acid production but\ndoes not reduce the level of uric acid if already elevated.15 Expert guidelines recommend use of rasburicase, a urate oxidase enzyme, for high-risk\npatients before initiating chemotherapy.11,16 For patients with spontaneous TLS, we did\nnot identify any clear expert-based guidelines for clinicians. This may be due to the rarity\nof the condition or the possibility of confounding causes of AKI unrelated to uric acid\nelevation. Use of rasburicase to prevent AKI seems physiologically intuitive, but high-level\nclinical evidence to support this effect is not present to date. In a nonrandomized study of\npediatric patients at high risk for developing TLS, one group trended changes in uric acid\nand creatinine while receiving either rasburicase or allopurinol, and the results favored\nimproved renal outcomes with the use of rasburicase.17 There has been one clinical trial evaluating the use of rasburicase in adult patients\nat risk for TLS, and the results did not show a reduced risk of developing an AKI. The study\ndid, however, show that rasburicase correlated with reduced laboratory TLS.18 There has been one meta-analysis performed in review of rasburicase based mostly on\ntrials in pediatric patients. Despite 5 pediatric trials showing a benefit in favor of\nrasburicase, it was determined that evidence was insufficient to promote the use of\nrasburicase to prevent TLS or AKI due to the inconclusive findings in a single randomized\nclinical trial.19 For our case, there is no evidence to guide a decision on whether or not to use\nrasburicase. Our case adds to a growing need to conduct randomized trials evaluating the use\nof rasburicase in both SPTLS and TLS.\n\nSummary\nIn summary, we have reported the first case of SPTLS in a patient with blastoid-variant\nMCL. We have reviewed the limitations, which many non-oncologist providers may encounter on\nrealization of this condition. Development of consensus diagnostic criteria and management\nguidelines for spontaneous TLS would be of benefit for non-oncology, general medicine\nproviders. More robust evidence is needed to clarify the role of rasburicase in patients at\nrisk for TLS and in theory, for those with SPTLS.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: At the University of Florida, institutional review board or ethic board approval is not\nrequired for publication of case reports that do not disclose identifiable patient\ninformation.\n\nInformed Consent: Written informed consent and verbal consent was obtained from the patient for their\nanonymized information to be published in this article.\n\nORCID iD: Vishal Patel \nhttps://orcid.org/0000-0003-3759-9523\n==== Refs\nReferences\n1 \nHande KR Garrow GC. \nAcute tumor lysis syndrome in patients with high-grade non-Hodgkin’s\nlymphoma\n. Am J Med .\n1993 ;94 :133 -139\n.8430709 \n2 \nMontesinos P Lorenzo I Martín G , et al\nTumor lysis syndrome in patients with\nacute myeloid leukemia: identification of risk factors and development of a predictive\nmodel\n. Haematologica .\n2008 ;93 :67 -74\n.18166787 \n3 \nKjellstrand CM Cambell DC von Hartitzsch B Buselmeier TJ. \nHyperuricemic acute renal failure\n. Arch Intern\nMed \n1974 ;\n133 :349 -359\n.4283735 \n4 \nShimada M Dass B Ejaz AA. \nParadigm shift in the role of uric acid in acute kidney\ninjury\n. Semin Nephrol .\n2011 ;31 :453 -458\n.22000653 \n5 \nShimabukuro-Vornhagen A Gödel P Subklewe M , et al\nCytokine release\nsyndrome\n. J Immunother Cancer .\n2018 ;6 :56 .29907163 \n6 \nCairo MS Bishop M. \nTumour lysis syndrome: new therapeutic strategies and\nclassification\n. Br J Haematol .\n2004 ;127 :3 -11\n.15384972 \n7 \nHoward SC Jones DP Pui CH. \nThe tumor lysis syndrome\n. N Engl J Med .\n2011 ;364 :1844 -1854\n.21561350 \n8 \nMato AR Riccio BE Qin L , et al\nA predictive model for the detection\nof tumor lysis syndrome during AML induction therapy\n. Leuk\nLymphoma .\n2006 ;47 :877 -883\n.16753873 \n9 \nCairo MS Coiffier B Reiter A Younes A ; TLS Expert Panel . Recommendations for the\nevaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children\nwith malignant diseases: an expert TLS panel consensus\n. Br J\nHaematol .\n2010 ;149 :578 -586\n.20331465 \n10 \nHahn K Kanbay M Lanaspa MA Johnson RJ Ejaz AA. \nSerum uric acid and acute kidney injury: a mini review\n.\nJ Adv Res .\n2017 ;8 :529 -536\n.28748118 \n11 \nDarmon M Vincent F Camous L , et al; Groupe de Recherche en Réanimation\nRespiratoire et Onco-Hématologique (GRRR-OH) . Tumour lysis\nsyndrome and acute kidney injury in high-risk haematology patients in the rasburicase\nera. A prospective multicentre study from the Groupe de Recherche en Réanimation\nRespiratoire et Onco-Hématologique\n. Br J Haematol .\n2013 ;162 :489 -497\n.23772757 \n12 \nShimada M Johnson RJ May WS Jr , et al\nA novel role for uric acid in acute\nkidney injury associated with tumour lysis syndrome\n. Nephrol\nDial Transplant .\n2009 ;24 :2960 -2964\n.19581334 \n13 \nSánchez-Lozada LG Tapia E Santamaría J , et al\nMild hyperuricemia induces\nvasoconstriction and maintains glomerular hypertension in normal and remnant kidney\nrats\n. Kidney Int .\n2005 ;67 :237 -247\n.15610247 \n14 \nKang DH Park SK Lee IK Johnson RJ. \nUric acid-induced C-reactive protein expression: implication on cell\nproliferation and nitric oxide production of human vascular cells\n.\nJ Am Soc Nephrol .\n2005 ;16 :3553 -3562\n.16251237 \n15 \nPacher P Nivorozhkin A Szabó C. \nTherapeutic effects of xanthine oxidase inhibitors: renaissance half a\ncentury after the discovery of allopurinol\n. Pharmacol\nRev .\n2006 ;58 :87 -114\n.16507884 \n16 \nCoiffier B Altman A Pui CH Younes A Cairo MS. \nGuidelines for the management of pediatric and adult tumor lysis syndrome:\nan evidence-based review\n. J Clin Oncol .\n2008 ;26 :2767 -2778\n.18509186 \n17 \nGoldman SC Holcenberg JS Finklestein JZ , et al\nA randomized comparison between\nrasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor\nlysis\n. Blood .\n2001 ;97 :2998 -3003\n.11342423 \n18 \nCortes J Moore JO Maziarz RT , et al\nControl of plasma uric acid in adults\nat risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and\nrasburicase followed by allopurinol compared with allopurinol alone—results of a\nmulticenter phase III study\n. J Clin Oncol .\n2010 ;28 :4207 -4213\n.20713865 \n19 \nCheuk DK Chiang AK Chan GC Hay SY. \nUrate oxidase for the prevention and treatment of tumour lysis syndrome in\nchildren with cancer\n. Cochrane Database Syst Rev .\n2017 ;(3 ): CD006945 .28272834\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "rasburicase; tumor lysis syndrome; uric acid nephropathy", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D058186:Acute Kidney Injury; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome; D014503:Urate Oxidase; D014527:Uric Acid", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620944709", "pmc": null, "pmid": "32720820", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28272834;16251237;29907163;19581334;20331465;15384972;4283735;18166787;28748118;20713865;18509186;23772757;15610247;22000653;16507884;21561350;8430709;16753873;11342423", "title": "Spontaneous Tumor Lysis Syndrome in Blastoid-Variant Mantle Cell Lymphoma: Considerations for the General Internist.", "title_normalized": "spontaneous tumor lysis syndrome in blastoid variant mantle cell lymphoma considerations for the general internist" }

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SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID-VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020?8:1-5. 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SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID?VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. 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SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID?VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020 JUL?8:1?5.", "literaturereference_normalized": "spontaneous tumor lysis syndrome in blastoid variant mantle cell lymphoma considerations for the general internist", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18193850, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-PFIZER INC-2020317840", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID-VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020?8:1-5", "literaturereference_normalized": "spontaneous tumor lysis syndrome in blastoid variant mantle cell lymphoma considerations for the general internist", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201111", "receivedate": "20200818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18161185, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" }, { "companynumb": "US-BAUSCH-BL-2020-023369", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORMAL SALINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RASBURICASE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MANTLE CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCTIVE COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSPNOEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "PATEL V, CASE R. SPONTANEOUS TUMOR LYSIS SYNDROME IN BLASTOID-VARIANT MANTLE CELL LYMPHOMA: CONSIDERATIONS FOR THE GENERAL INTERNIST. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020?8:1-5. DOI:10.1177/2324709620944709", "literaturereference_normalized": "spontaneous tumor lysis syndrome in blastoid variant mantle cell lymphoma considerations for the general internist", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201119", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18178693, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]

{ "abstract": "In cases of severe acetaminophen-induced acute liver failure and hepatic encephalopathy, liver transplant can be the only real hope for neurologic recovery and indeed survival. In such cases, the bioethical principles of beneficence and justice often come into conflict. This article examines a case in which a neurologist managing an acetaminophen-overdose patient in the neurologic intensive care unit is faced with a conflict between her patient's need for a liver transplant and the needs of other patients on the transplant list.", "affiliations": null, "authors": "Willey|Joshua Z|JZ|;Tolchin|Benjamin David|BD|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1212/01.CON.0000450974.91699.b8", "fulltext": null, "fulltext_license": null, "issn_linking": "1080-2371", "issue": "20(3 Neurology of Systemic Disease)", "journal": "Continuum (Minneapolis, Minn.)", "keywords": null, "medline_ta": "Continuum (Minneap Minn)", "mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D026686:Beneficence; D062787:Drug Overdose; D006501:Hepatic Encephalopathy; D006801:Humans; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012935:Social Justice", "nlm_unique_id": "9509333", "other_id": null, "pages": "681-5", "pmc": null, "pmid": "24893242", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Liver transplant for intentional acetaminophen overdose and hepatic encephalopathy: a conflict between beneficence and justice.", "title_normalized": "liver transplant for intentional acetaminophen overdose and hepatic encephalopathy a conflict between beneficence and justice" }

[ { "companynumb": "PHHY2015US036277", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETYLCYSTEINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLCYSTEINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MANNITOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MANNITOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAXIMIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAXIMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LACTULOSE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACTULOSE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WILLEY JZ, TOLCHIN BD.. LIVER TRANSPLANT FOR INTENTIONAL ACETAMINOPHEN OVERDOSE AND HEPATIC ENCEPHALOPATHY: A CONFLICT BETWEEN BENEFICENCE AND JUSTICE.. CONTINUUM LIFELONG LEARNING IN NEUROLOGY. 2014;20(3):681-685", "literaturereference_normalized": "liver transplant for intentional acetaminophen overdose and hepatic encephalopathy a conflict between beneficence and justice", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150326", "receivedate": "20150326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10958193, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]

{ "abstract": "Eosinophilic dermatosis of hematological malignancy is a paraneoplastic skin eruption associated with chronic lymphocytic leukemia and other B-cell malignancies. It clinically resembles an insect bite reaction and it can precede the symptoms of the hematological malignancy or be related to a more aggressive course. Different treatments have been proposed, but partial response and recurrence are frequent. Herein, we describe a case of eosinophilic dermatosis associated with mantle cell lymphoma with remission after lenalidomide therapy.", "affiliations": "Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.;Oncology Center, Portuguese Beneficence of São Paulo, Sao Paulo, Brazil.;Department of Dermatology, Federal University of Sao Paulo, Sao Paulo, Brazil.", "authors": "Sato-Sano|Marcelo|M|https://orcid.org/0000-0003-2934-6729;Teixeira|Solange Pistori|SP|;Vargas|Juliano Cordova|JC|;Baiocchi|Otávio Cesar Carvalho Guimarães|OCCG|;Enokihara|Milvia Maria Simões E Silva|MMSES|;Gomes|Elimar Elias|EE|;Batista|Mariana Dias|MD|", "chemical_list": "D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1111/1346-8138.14916", "fulltext": null, "fulltext_license": null, "issn_linking": "0385-2407", "issue": "46(7)", "journal": "The Journal of dermatology", "keywords": "eosinophilic dermatosis of hematological malignancy; eosinophilic reactive dermatoses; hematological malignancies; lenalidomide; paraneoplastic disorders", "medline_ta": "J Dermatol", "mesh_terms": "D004802:Eosinophilia; D005076:Exanthema; D006801:Humans; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D011537:Pruritus; D012867:Skin; D016896:Treatment Outcome", "nlm_unique_id": "7600545", "other_id": null, "pages": "618-621", "pmc": null, "pmid": "31144726", "pubdate": "2019-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lenalidomide in the management of eosinophilic dermatosis of hematological malignancy.", "title_normalized": "lenalidomide in the management of eosinophilic dermatosis of hematological malignancy" }

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{ "abstract": "This case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis.", "affiliations": "Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of General Internal Medicine, Department of Medicine, Medstar Georgetown University Hospital, Washington DC, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.;Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA, USA.", "authors": "Genovese|Leonard|L|https://orcid.org/0000-0002-0950-9861;Dey|Amit K|AK|;Cole|Robert T|RT|;Cooper|Lauren B|LB|;Desai|Shashank|S|;May|Christopher W|CW|;Sarin|Eric|E|;Shah|Palak|P|;Sinha|Shashank S|SS|;Psotka|Mitchell A|MA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/20009666.2021.1948668", "fulltext": "\n==== Front\nJ Community Hosp Intern Med Perspect\nJ Community Hosp Intern Med Perspect\nJournal of Community Hospital Internal Medicine Perspectives\n2000-9666\nTaylor & Francis\n\n10.1080/20009666.2021.1948668\n1948668\nVersion of Record\nCase Report\nCase Report\nFulminant cardiogenic shock due to cardiac sarcoidosis\nL. GENOVESE ET AL.\nJOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES\nhttps://orcid.org/0000-0002-0950-9861\nGenovese Leonard a\nDey Amit K. b\nCole Robert T. a\nCooper Lauren B. a\nDesai Shashank a\nMay Christopher W. a\nSarin Eric a\nShah Palak a\nSinha Shashank S. a\nPsotka Mitchell A. a\na Division of Cardiology, Inova Heart and Vascular Institute , Falls Church, VA, USA\nb Division of General Internal Medicine, Department of Medicine, Medstar Georgetown University Hospital , Washington DC, USA\nCONTACT Leonard Genovese leonard.genovese@inova.org Inova Heart and Vascular Institute , 3300 Gallows Road, Falls Church, VA 22042\nTwitter: @lenny_genovese\n\nTweet: A Case of Rapidly Progressive Cardiogenic #Shock Due to Cardiac #Sarcoidosis @lenny_genovese @mpsotka @shashanksinhamd @doctorrtc @lbcooper @ihvinews\n\nABBREVIATIONS\n\nECMO: extracorporeal membrane oxygenation; LVEF: left ventricular ejection fraction; cMRI: cardiac magnetic resonance imaging\n\n20 9 2021\n2021\n20 9 2021\n11 5 673677\nIntegra13 9 2021\nIntegra13 9 2021\n26 3 2021\n23 6 2021\n© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nThis case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis.\n\nKEYWORDS\n\nCardiac sarcoidosis\nheart failure\ncardiogenic shock\nheart transplantation\n==== Body\npmc1. Case presentation\n\nA 57-year-old man with a medical history significant only for hypercholesterolemia presented to a cardiology clinic with 6 months of progressive exercise intolerance manifest as a gradual increase in his 1-mile running time and a decline from running 30 miles to less than 3 miles each week. Days later, outpatient coronary angiography showed non-obstructive coronary atherosclerosis and ventriculogram left ventricular ejection fraction (LVEF) was 45%. The patient was started on carvedilol and aspirin.\n\nOne week later, he awoke with acute left-sided chest pain. Emergent electrocardiography demonstrated sinus tachycardia and ST-segment elevations and repolarization abnormalities (Figure 1). Repeat coronary angiography revealed no change, but LVEF by ventriculography had declined to 20%. Post-procedurally, he developed hypotension requiring initiation of vasopressors and hemodynamically unstable wide-complex tachycardia requiring defibrillation. He was transferred to our hospital for further management.Figure 1. Electrocardiograms\n\nLegend: Figure A shows baseline electrocardiogram from outpatient clinic. Figure B is the electrocardiogram at presentation to hospital demonstrating ST segment elevations in the anterior precordial leads with ST segment depressions in the lateral leads.\n\nOn arrival, the patient was comfortable but mean arterial pressure was 55 mmHg off vasopressors. Jugular venous pressure was elevated, breath sounds were decreased in the bilateral lung bases, and heart sounds were distant without evidence of a murmur or gallop. His extremities were cool. Arterial blood gas showed a pH of 7.4, PaCO2 of 29 mmHg, PaO2 of 63 mmHg on ambient air, bicarbonate of 20 mEq/L, lactate of 4.0 mmol/L, troponin I of 2.0 ng/mL, B-type natriuretic peptide of 2600 pg/mL, and a creatinine of 1.4 mg/dL increased from a baseline of 1.0 mg/dL. A Swan-Ganz catheter was placed revealing a right atrial pressure of 20 mmHg and pulmonary capillary wedge pressure of 22 mmHg. Pulmonary artery oxygen saturation was 40% and calculated cardiac output using the estimated Fick formula was 2.4 L/min, with cardiac index of 1.1 L/min/m2. Given the acuity of presentation and the rapidity of clinical decline, urgent laboratory testing and imaging studies were performed.\n\nTransthoracic echocardiography showed biventricular dysfunction and dilation with global hypokinesis, without asymmetric myocardial thickening or structural valvular disease. There was biatrial dilation. Thyroid panel, cortisol, hemoglobin A1c, iron studies including ferritin, and autoimmune antibody levels were normal, while human immunodeficiency virus, Borrelia burgdorferi, respiratory viral panel, and blood culture testing were negative. Urinary toxicology was negative. C-reactive protein was elevated at 13.9 mg/dL. Cardiac myocardial resonance imaging (cMRI) demonstrated patchy gadolinium delayed enhancement within the right and left ventricular myocardia and pericardial thickening with enhancement, consistent with myocarditis or infiltrative disease though without T2-weighted evidence of edema (Figure 2). Endomyocardial biopsy was not pursued due to the patient’s hemodynamic and electrical instability.Figure 2. Cardiac magnetic resonance imaging\n\nLegend: Cardiac magnetic resonance imaging with myocardial delayed gadolinium enhancement in T1 weighted imaging: Figure A, anterior right ventricular enhancement (red arrow). Figure B, pericardial thickening with pericardial enhancement (blue arrows).\n\nFigure 3. Photomicrographs of explanted cardiac myocardium\n\nLegend: Figure A: Right ventricular myocardium with large areas of hypercellularity and extensive fibrosis (red arrows) with granuloma formation (blue arrows). Figure B: Left ventricular granulomas (blue arrows) with surrounding fibrosis and hypercellularity.\n\nMilrinone and furosemide infusions were initiated, nitroprusside was added, and an intra-aortic balloon pump was eventually implanted for persistent cardiogenic shock (Table 1). He remained oliguric, and continued to have atrial and ventricular arrhythmias requiring defibrillation despite amiodarone infusion. Though the differential diagnoses of sarcoidosis and giant cell myocarditis were discussed, the patient was not initiated on corticosteroids. Due to continued hemodynamic and electrical instability he was femorally cannulated for veno-arterial extracorporeal membrane oxygenation (ECMO). Upon transplantation, pathological examination of the explanted heart revealed diffuse biventricular fibrosis, non-caseating granulomas, and multi-nucleated giant cells consistent with severe cardiac sarcoidosis (Figure 3).Table 1. Invasive hemodynamics\n\nIntervention\tLactate (mmol/L)\tMAP\n(mmHg)\tRAP\n(mmHg)\tPAP\n(mmHg)\tPAWP\n(mmHg)\tSvO2\n(%)\tCO/CI\n(Fick)\t\nNone\t4.0\t85\t20\t30/17\n(mean 25)\t22\t40\t2.38/1.13\t\nMilrinone\n0.5 mcg/kg/min\t3.4\t80\t18\t32/22\n(mean 25)\t22\t57\t3.43/1.63\t\n+ Nitroprusside 3 mcg/kg/min\t3.7\t71\t12\t30/21\n(mean – 24)\t21\t50\t3.59/1.71\t\n+ IABP at 1:1\t5.1\t64\t13\t27/13\n(mean – 18)\t10\t37\t3.05/1.45\t\nMAP = Mean arterial pressure; SvO2 = Mixed venous oxygen saturation; CO/CI = Cardiac output/cardiac index; IABP = intra-aortic balloon pump; PAP = Pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; RAP = right atrial pressure\n\nThe patient was discharged home from the hospital two weeks after transplant and continues to do well. He has completed cardiac rehabilitation and started running again. His immunosuppression regimen consists of prednisone 5 mg daily, tacrolimus 2 mg twice daily, and mycophenolate 1000 mg twice daily. He has not had allograft rejection.\n\n2. Discussion\n\nSarcoidosis is a multisystem granulomatous disease of unknown etiology that may affect any organ system. It has an estimated prevalence of about 200,000 people in the USA [1]. Noncaseating granulomas are the pathologic hallmark of the disease, and it most commonly presents with pulmonary and lymphatic disease. Although autopsy studies have uncovered cardiac involvement in 25% of patients with sarcoidosis, the true prevalence may be underappreciated [1]. The three principal sequelae of myocardial damage due to sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure, which can be insidious or fulminant [1]. Diagnosis of CS can be challenging, as there are multiple proposed clinical criteria without a gold standard [1]. Nevertheless, the mainstays of diagnosis include cardiac MRI with gadolinium for myocardial fibrosis and edema, and fluorodeoxyglucose positron emission tomography for myocardial inflammation. Endomyocardial biopsy has excellent specificity but an estimated sensitivity of less than 30%, and some severe cases are only diagnosed post-mortem.\n\nPatients with CS generally have a poorer prognosis than patients with sarcoidosis but without cardiac involvement, and left ventricular function appears to predict survival. Of patients with CS and normal ventricular function 89% survive to 10 years compared to 27% of patients with systolic dysfunction [1]. The diffuse myocardial fibrosis and granulomas with biventricular dilation and dysfunction in this case are consistent with longstanding unrecognized and life-threatening disease.\n\nThe mainstay of treatment for CS includes immunosuppression, typically with corticosteroids and variably with steroid-sparing agents such as methotrexate or infliximab [2]. In combination with immunosuppression, antiarrhythmic medications including amiodarone or sotalol and ablation procedures can be used for CS-associated ventricular arrhythmias. However, ventricular tachycardia ablation in CS has had varied success and frequently is associated with recurrence [3,4] because of ongoing inflammation or progressive myocardial scarring. Given the propensity for ventricular arrhythmias and risk of sudden cardiac death, implantable cardioverter-defibrillator therapy may be considered in a broad array of situations according to expert consensus recommendations [5]. Orthotopic heart transplant may be indicated in severe cases of CS unresponsive to drug and device therapy. CS recurrence after transplant is rare and may be prevented with long-term corticosteroid use. Nevertheless, patients with CS have similar rates of rejection and overall survival as patients transplanted due to other cardiomyopathies [2].\n\n3. Conclusions\n\nCardiac sarcoidosis rarely presents as refractory cardiogenic shock. This case highlights the need to include CS in the differential diagnosis of patients with cardiomyopathy, even if there is no evidence of extracardiac disease. Findings on advanced cardiac imaging can help determine the potential etiology of a non-ischemic cardiomyopathy, including sarcoidosis. Though he presented acutely, in this case CS was likely progressive over a longer period of time than his months of symptoms, and perhaps could have been treated with immunosuppression if identified earlier.\n\n4. Learning objectives\n\nCardiac sarcoidosis may be difficult to diagnose and can present as rapidly progressive heart failure with cardiogenic shock.\n\nYoung patients with an otherwise unknown etiology of cardiomyopathy would likely benefit from advanced cardiac imaging with FDG-PET or MRI, which may assist with diagnosis if a high diagnostic suspicion of cardiac sarcoidosis or other infiltrative disease is maintained.\n\nThe three most common presentations of cardiac sarcoidosis are heart failure, ventricular arrhythmias, and conduction abnormalities.\n\nThe mainstays of therapy for cardiac sarcoidosis include immunosuppression with corticosteroids and frequently steroid-sparing agents.\n\nAmiodarone and sotalol are the most common antiarrhythmics used to suppress ventricular arrhythmias; ventricular ablation has demonstrated mixed results.\n\nSevere refractory cardiac sarcoidosis may require heart transplantation though sarcoidosis can recur in the donor heart.\n\nDisclosure statement\n\nNo potential conflict of interest was reported by the author(s).\n==== Refs\nReferences\n\n[1] Ribeiro NetoML, JellisCL, JoyceE, et al. Update in cardiac sarcoidosis. Ann Am Thorac Soc. 2019 Nov;16 (11 ):1341–1350. .31322914\n[2] RosenthalDG, AndersonME, PetekBJ, et al. Invasive hemodynamics and rejection rates in patients with cardiac sarcoidosis after heart transplantation. Can J Cardiol. 2018 Aug;34 (8 ):978–982. Epub 2018 Apr 6. .30049365\n[3] JeficD, JoelB, GoodE, et al. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry. Heart Rhythm. 2009 Feb;6 (2 ):189–195. Epub 2008 Oct 30.19187909\n[4] KoplanBA, SoejimaK, BaughmanK, et al. Refractory ventricular tachycardia secondary to cardiac sarcoid: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm. 2006 Aug;3 (8 ):924–929. Epub 2006 Mar 30.16876741\n[5] BirnieDH, SauerWH, BogunF, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014 July;11 (7 ):1305–1323. Epub 2014 May 9.24819193\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2000-9666", "issue": "11(5)", "journal": "Journal of community hospital internal medicine perspectives", "keywords": "Cardiac sarcoidosis; cardiogenic shock; heart failure; heart transplantation", "medline_ta": "J Community Hosp Intern Med Perspect", "mesh_terms": null, "nlm_unique_id": "101601396", "other_id": null, "pages": "673-677", "pmc": null, "pmid": "34567462", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "19187909;16876741;30049365;24819193;31322914", "title": "Fulminant cardiogenic shock due to cardiac sarcoidosis.", "title_normalized": "fulminant cardiogenic shock due to cardiac sarcoidosis" }

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{ "abstract": "Mycobacterium avium-intracellulare complex (MAC) infections are well known in immunocompromised patients, notably in human immunodeficiency virus infection, but remain scarcely described in kidney transplantation. Moreover, cutaneous involvement in this infection is very unusual. We describe here a disseminated infection caused by MAC in a kidney transplant recipient revealed by cutaneous lesions. This case highlights the need for an exhaustive, iterative microbiologic workup in the context of an atypical disease presentation in a renal transplant patient, regardless of the degree of immunosuppression.", "affiliations": "Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Service d'anatomopathologie, Hôpital Cochin, Université Paris Descartes, APHP, Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.;Service d'hépatologie, Hôpital Cochin, Université Paris Descartes, APHP, Paris, France.;Service de dermatologie, Hôpital Cochin, Pavillon Tarnier, Université Paris Descartes, APHP, Paris, France.;Service de transplantation rénale, Hôpital Necker Enfants Malades, Université Paris Descartes, APHP, Paris, France.;Service de dermatologie, Hôpital Cochin, Pavillon Tarnier, Université Paris Descartes, APHP, Paris, France.;Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, IHU Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.", "authors": "Fadlallah|J|J|;Rammaert|B|B|;Laurent|S|S|;Lanternier|F|F|;Pol|S|S|;Franck|N|N|;Mamzer|M F|MF|;Dupin|N|N|;Lortholary|O|O|", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/tid.12478", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "18(1)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "Mycobacterium avium-intracellulare complex; cutaneous infection; immunodeficiency; kidney transplantation; non-tuberculous mycobacteria", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D066027:Transplant Recipients", "nlm_unique_id": "100883688", "other_id": null, "pages": "105-11", "pmc": null, "pmid": "26540585", "pubdate": "2016-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Mycobacterium avium complex disseminated infection in a kidney transplant recipient.", "title_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016; 18(1): 105-111", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160411", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12191524, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-WATSON-2016-05976", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE (UNKNOWN)" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECT DIS. 2016;18(1):105-11", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160415", "receivedate": "20160322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12200097, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-MYLANLABS-2016M1016414", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG/DAY; LAST 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG/DAY; LAST 10 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N, ET AL. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPL-INFECT-DIS 2016;18(1):105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160428", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12301367, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "FR-BAUSCH-BL-2016-006447", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40065", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, FRANCK N. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016?18(1):105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12196970, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2016-01097", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090033", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090033", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "0202532", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GM", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078939", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LORTHOLARY O, FADLALLAH J, RAMMAERT B, LAURENT S, LANTERNIER F, POL S, DUPIN N, FRANCK N, MAMZER M. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2015;18:105-111.", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160402", "receivedate": "20160402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12232751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "FR-PFIZER INC-2016149359", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFABUTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050689", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFABUTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis toxic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic cirrhosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FADLALLAH, J.. MYCOBACTERIUM AVIUM COMPLEX DISSEMINATED INFECTION IN A KIDNEY TRANSPLANT RECIPIENT. TRANSPLANT INFECTIOUS DISEASE. 2016;18 (1):105-111", "literaturereference_normalized": "mycobacterium avium complex disseminated infection in a kidney transplant recipient", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20161117", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12196833, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "Thrombocytosis has been feared as a source of thrombotic complications during the conduct of cardiopulmonary bypass (CPB) for patients undergoing cardiac procedures. We present a patient urgently requiring repair/replacement of three heart valves that had preexisting myelofibrosis with thrombocytosis (platelet count of 800,000 per µl) and neutrophilia (40,000 per µl). Despite achieving an activated clotting time > 500 s with heparin and antithrombin concentrate administration prior to CPB, the pump oxygenator and reservoir demonstrated significant clot just prior to restoration of the patient's circulation. The patient subsequently suffered a severe protamine reaction that was successfully managed. A review of the literature of similar patients and the relevant cellular and biochemical mechanisms in this setting are presented, with potential therapeutic approaches to prevent such complications noted.", "affiliations": "Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA. vgnielsen333@gmail.com.;Departments of Anesthesiology and Surgery, The University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA.;Perfusion Department, Banner University Medical Center Tucson, Tucson, AZ, USA.", "authors": "Nielsen|Vance G|VG|http://orcid.org/0000-0002-8072-9883;Kazui|Toshinobu|T|;Horn|Evan A|EA|;Dotson|Victoria E|VE|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1007/s11239-021-02574-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0929-5305", "issue": "52(4)", "journal": "Journal of thrombosis and thrombolysis", "keywords": "Cardiopulmonary bypass; Neutrophilia; Platelet factor 4; Thrombocytosis; Thrombosis", "medline_ta": "J Thromb Thrombolysis", "mesh_terms": null, "nlm_unique_id": "9502018", "other_id": null, "pages": "1220-1226", "pmc": null, "pmid": "34581944", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": "10915475;15334759;3485946", "title": "Thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass: a case report and literature review.", "title_normalized": "thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass a case report and literature review" }

[ { "companynumb": "US-Fresenius Kabi-FK202114210", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROTAMINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089454", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Infusion", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Procoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "350", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROTAMINE SULFATE" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary hypertension", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Nielsen V, Kazui T, Horn E, Dotson V. Thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass: a case report and literature review. Journal of Thrombosis and Thrombolysis. 2021;52:1220-1226.", "literaturereference_normalized": "thrombocytosis and neutrophilia associated with oxygenator failure and protamine reaction after cardiopulmonary bypass a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20202348, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "We report the case of a 10-year-old child treated for latent tuberculosis infection (LTBI) with pyrazinamide (PZA) and levofloxacin after contact with a smear-positive multidrug-resistant tuberculosis adult. Over the course of the treatment, the patient developed a drug-induced fulminant hepatitis attributed to the combination of PZA and levofloxacin. This case highlights the hepatotoxicity of the association of second-line anti-TB treatment in children.", "affiliations": "From the Service d'Urgences et de Réanimation Pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Service des maladies infectieuses, Hôpital de la Croix Rousse, Groupement Hospitaliser Nord, Hospices Civils de Lyon, Université Claude Bernard Lyon, Lyon, France.;Service de Pneumologie pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Bron, France.;From the Service d'Urgences et de Réanimation Pédiatrique, Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.", "authors": "Huguet|Annabelle|A|;Ader|Florence|F|;Ohlmann|Camille|C|;Collardeau-Frachon|Sophie|S|;Gillet|Yves|Y|", "chemical_list": "D000995:Antitubercular Agents; D011718:Pyrazinamide; D064704:Levofloxacin", "country": "United States", "delete": false, "doi": "10.1097/INF.0000000000002413", "fulltext": null, "fulltext_license": null, "issn_linking": "0891-3668", "issue": "38(10)", "journal": "The Pediatric infectious disease journal", "keywords": null, "medline_ta": "Pediatr Infect Dis J", "mesh_terms": "D000995:Antitubercular Agents; D002648:Child; D004359:Drug Therapy, Combination; D006801:Humans; D055985:Latent Tuberculosis; D064704:Levofloxacin; D008297:Male; D047508:Massive Hepatic Necrosis; D011718:Pyrazinamide; D018088:Tuberculosis, Multidrug-Resistant", "nlm_unique_id": "8701858", "other_id": null, "pages": "1025-1026", "pmc": null, "pmid": "31335574", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Drug-Induced Fulminant Hepatitis in a Child Treated for Latent Multidrug-Resistant Tuberculosis With Dual Therapy Combining Pyrazinamide and Levofloxacin.", "title_normalized": "drug induced fulminant hepatitis in a child treated for latent multidrug resistant tuberculosis with dual therapy combining pyrazinamide and levofloxacin" }

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DRUG-INDUCED FULMINANT HEPATITIS IN A CHILD TREATED FOR LATENT MULTIDRUG-RESISTANT TUBERCULOSIS WITH DUAL THERAPY COMBINING PYRAZINAMIDE AND LEVOFLOXACIN. 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DRUG-INDUCED FULMINANT HEPATITIS IN A CHILD TREATED FOR LATENT MULTIDRUG-RESISTANT TUBERCULOSIS WITH DUAL THERAPY COMBINING PYRAZINAMIDE AND LEVOFLOXACIN.. PEDIATR. INFECT. DIS. 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{ "abstract": "Pulmonary air leak syndromes are extremely rare complications of systemic autoimmune connective tissue diseases and the occurrence of spontaneous subcutaneous emphysema (SSE) from pulmonary leak in the absence of pneumothorax or pneumomediastinum is even rarer. We report a case of recurrent SSE in a patient with rheumatoid arthritis and interstitial lung disease. The SSE was managed conservatively each time and it resorbed over several days. There has been no previous documented report of SSE in the absence of pneumomediastinum, pneumothorax or pulmonary nodules in a patient with RA.", "affiliations": "Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.;Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria.;Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.;Rheumatology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.", "authors": "Adelowo|Olufemi|O|;Akintayo|Richard Oluyinka|RO|;Olaosebikan|Hakeem|H|;Oba|Rasheedat|R|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D035583:Rare Diseases; D012008:Recurrence; D013352:Subcutaneous Emphysema; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26472288", "pubdate": "2015-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10091485;19916579;9267111;17764060;22767622;10858424;6375617;24761533;15729122;15026583;10784520;10092167;24231065;3343723;17136544;18311044", "title": "Recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis.", "title_normalized": "recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis" }

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{ "abstract": "A 46-year-old female with no previous personal or family psychiatric history underwent endoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) to treat pain related to cystic fibrosis transmembrane conductance regulator-associated chronic pancreatitis. She had excellent response to her first three CPBs using bupivacaine and triamcinolone. The patient's subsequent CPBs were complicated by symptoms of racing thoughts, delusional thinking, and insomnia. She was diagnosed with acute psychosis secondary to triamcinolone. This is the first reported case of steroid-induced psychosis caused by EUS-guided CPB. Optimal treatment for steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroids and administration of lithium, valproic acid, or atypical antipsychotics.", "affiliations": "Department of Gastroenterology, Carolinas Medical Center, Charlotte, NC.;Department of Gastroenterology, Carolinas Medical Center, Charlotte, NC.", "authors": "Olson|David C|DC|;Lewis|Jason J|JJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.14309/crj.2017.11", "fulltext": "\n==== Front\nACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.1110.14309/crj.2017.11Case ReportPancreasSteroid-Induced Psychosis after EUS-Guided Celiac Plexus Blockade Olson et alSteroid-Induced Psychosis Following EUS-Guided CPBOlson David C. MDLewis Jason J. MDDepartment of Gastroenterology, Carolinas Medical Center, Charlotte, NCCorrespondence: David C. Olson, Carolinas Medical Center, 1000 Blythe Blvd, MEB 5th Floor, Charlotte, NC 28210 (David.Olson@carolinas.org).2017 18 1 2017 4 e1112 8 2016 14 11 2016 Copyright © Olson et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/A 46-year-old female with no previous personal or family psychiatric history underwent endoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) to treat pain related to cystic fibrosis transmembrane conductance regulator-associated chronic pancreatitis. She had excellent response to her first three CPBs using bupivacaine and triamcinolone. The patient’s subsequent CPBs were complicated by symptoms of racing thoughts, delusional thinking, and insomnia. She was diagnosed with acute psychosis secondary to triamcinolone. This is the first reported case of steroid-induced psychosis caused by EUS-guided CPB. Optimal treatment for steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroids and administration of lithium, valproic acid, or atypical antipsychotics.\n==== Body\nIntroduction\nEndoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) and neurolysis were first described in 1996 and have since been shown to be effective procedures for the management of abdominal pain in the setting of chronic pancreatitis and pancreatic cancer, respectively.1,2 The most common complications following EUS-guided CPB include transient symptoms such as self-limited diarrhea and hypotension.3\n\nCase Report\nA 46-year-old woman with no previous personal or family psychiatric history underwent EUS-guided CPB to treat severe pain from chronic pancreatitis related to mutations in the cystic fibrosis transmembrane conductance regulator (CTFR) gene. In addition to opioid pain management, the patient underwent successful EUS-guided CPBs at 4-month intervals and had received 3 CPBs in the previous 13 months. Her procedures were performed via the standard transgastric approach. Color Doppler guidance was used to confirm a lack of significant vascular structures within the injection needle path, and needle aspiration was performed prior to injection to exclude entry into a blood vessel (Figure 1). A total of 20 mL 0.25% bupivacaine and 2 mL 40 mg/mL triamcinolone (80 mg) were injected in the area of the celiac plexus using a 20-gauge needle during each procedure (Figure 2).\n\nFigure 1 EUS image identifying the celiac axis with lack of significant vascular structures within the injection needle path.\n\nFigure 2 EUS image showing successful injection of triamcinolone/bupivacaine in the area of the celiac plexus.\n\nThe patient tolerated her first 3 procedures well and achieved excellent pain relief without any significant post-procedural complications. After her fourth EUS-guided CPB, the patient noticed racing thoughts for 2 weeks. These symptoms resolved spontaneously, and she did not share her symptoms with her treating physicians. After her next procedure, the patient began experiencing symptoms of mania, including racing thoughts, delusional thinking, pressured speech, extreme anger, and insomnia. She also developed severe depression and anxiety, with 1 episode of suicidal ideation. She was subsequently diagnosed with acute psychosis secondary to triamcinolone and newly diagnosed bipolar disorder. The patient was treated with clonazepam and lithium, with complete resolution of her symptoms after several weeks. Following multidisciplinary review, it was felt that the risk of recurrent psychosis following subsequent CPBs outweighed the potential benefit of any temporary pain relief the patient received. The patient subsequently underwent a total pancreatectomy and has had an uneventful medical and psychiatric post-operative course.\n\nDiscussion\nThis is the first reported case of acute steroid-induced psychosis caused by EUS-guided CPB. While steroid-induced psychosis after administration of systemic corticosteroids has been extensively reported since the introduction of corticosteroids in the early 1950s, psychosis from regional administration is much more rare.4 Episodes of acute psychosis following epidural, intramuscular, and intraarticular corticosteroid administration have been reported.5-7 To our knowledge, only two cases of acute psychosis following regional CPB have been reported.8 In both of these cases, the patients received an anesthesiologist-administered CPB with triamcinolone via a posterior approach under fluoroscopic guidance. Additionally, both patients also had a known history of steroid-induced psychosis from previous systemic corticosteroid administration.\n\nThe pathophysiology by which corticosteroids cause psychosis is not fully understood. Suppression of the hypothalamus-pituitary axis and enhanced dopamine neurotransmission has been postulated as a cause.9 Decreased hippocampal volume has been demonstrated in patients receiving chronic corticosteroid therapy for >6 months, leading some to suggest that the action of corticosteroids at steroid-specific receptors in the hippocampus results in a decreased ability to filter irrelevant stimuli.10,11 Risk factors for the development of steroid-induced psychosis are not known. A history of psychiatric illness and previous courses of corticosteroids had been hypothesized to increase risk, but both of these predictors appear to be unreliable.10 There are no reported associations between psychiatric disease or acute psychosis and the presence of CTFR mutations. Optimal treatment for patients presenting with steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroid therapy and administration of lithium, valproic acid, neuroleptics, or atypical antipsychotics.12 Most patients will have improvement of symptoms within 2 weeks of initiation of treatment.\n\nAs the patient in this case received a combination of corticosteroids and local anesthetic, it is important to note that local anesthetics have also been associated with psychological phenomena. Several cases of patients experiencing hallucinations following administration of lidocaine, procainamide, bupivacaine, mepivacaine, and procaine for the purpose of regional anesthesia, pain relief, or management of ectopies have been reported.13 However, the majority of these patients experienced vivid fear of imminent death or delusional beliefs of having died rather than overt psychosis.\n\nIt is important for endoscopists to be aware of the potential adverse side effects associated with steroid administration following EUS-guided CPB. While steroid-induced psychosis from EUS-guided CPB appears to be a rare entity, prompt recognition and treatment will help prevent further complications from untreated symptoms and repeated steroid administrations.\n\nDisclosures\nAuthor contributions: DC Olson wrote and revised the manuscript. JJ Lewis edited the manuscript and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1. Wiersema MJ , Wiersema LM \nEndosonography-guided celiac plexus neurolysis . Gastrointest Endosc . 1996 ;\n44 :656 –62 .8979053 \n2. Kaufman M , Singh G , Das S , et al \nEfficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer . J Clin Gastroenterol . 2010 ;\n44 :127 –34 .19826273 \n3. Fabbri C , Luigiano C , Lisotti A , et al \nEndoscopic ultrasound-guided treatments: Are we getting evidence based - a systematic review . World J Gastroentero . 2014 ;\n20 (26 ):8424 –48 .\n4. Hall RC , Popkin MK , Stickney SK , et al \nPresentation of the steroid psychoses . J Nerv Ment Dis . 1979 ;\n167 :229 –36 .438794 \n5. Benyamin RM , Vallejo R , Kramer J , et al \nCorticosteroid induced psychosis in the pain management setting . Pain Physician . 2008 ;\n11 (6 ):917 –20 .19057637 \n6. Teuber I , Freiwald D , Volz HP \nAcute paranoid symptoms following intramuscular injection of nandrolone . Psychiatr Prax . 2003 ;\n30 (Suppl 2 ):73 –4 .13130341 \n7. Robinson DE , Harrison-Hansley E , Spencer RF \nSteroid psychosis after an intra-articular injection . Ann Rheum Dis . 2000 ;\n59 (11 ):927 .\n8. Fishman SM , Catarau EM , Sachs G , et al \nCorticosteroid-induced mania after single regional application at the celiac plexus . Anesthesiology . 1996 ;\n85 :1194 –6 .8916839 \n9. Schatzberg AF , Rothschild AJ , Langlais PJ , et al \nA corticosteroid/dopamine hypothesis for psychotic depression and related states . J Psychiatr Res . 1985 ;\n19 (1 ):57 –64 .2859366 \n10. Naber D , Sand P , Heigl B \nPsychopathological and neuropsychological effects of 8-days' corticosteroid treatment. A prospective study . Psychoneuroendocrinology . 1996 ;\n21 (1 ):25 –31 .8778901 \n11. Brown ES , J Woolston D , Frol A , et al \nHippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy . Biol Psychiatry . 2004 ;\n55 (5 ):538 –45 .15023583 \n12. Brown ES , Chandler PA \nMood and cognitive changes during systemic corticosteroid therapy . Prim Care Companion J Clin Psychiatry . 2001 ;\n3 :17 –21 .15014624 \n13. Marsch SC , Schaefer HG , Castelli I \nUnusual psychological manifestation of systemic local anesthetic toxicity . Anesthesiology . 1998 ;\n88 (2 ):531 –3 .9477077\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2326-3253", "issue": "4()", "journal": "ACG case reports journal", "keywords": null, "medline_ta": "ACG Case Rep J", "mesh_terms": null, "nlm_unique_id": "101638398", "other_id": null, "pages": "e11", "pmc": null, "pmid": "28144616", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "2859366;8778901;15014624;438794;9477077;13130341;25024600;8916839;19057637;15023583;8979053;11203422;19826273", "title": "Steroid-Induced Psychosis after EUS-Guided Celiac Plexus Blockade.", "title_normalized": "steroid induced psychosis after eus guided celiac plexus blockade" }

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STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG-CASE-REP-J 2017;4(2):1-3.", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170526", "receivedate": "20170526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13587355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-AKORN PHARMACEUTICALS-2017AKN00750", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "202374", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "80 MG, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NERVE BLOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 ML, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NERVE BLOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Substance-induced psychotic disorder", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON D, LEWISH J. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG CASE REP J (DOI 10.14309/CRJ.2017.11). 2017;4(2):ARTICLE #1-3, E11", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170613", "receivedate": "20170613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13647323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK026558", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 ML 40 MG/ML TRIAMCINOLONE (80 MG), EUS-GUIDED CPBS AT 4-MONTH INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 ML, EUS-GUIDED CPBS AT 4-MONTH INTERVALS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPIVACAINE." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLSON DC, LEWIS JJ. STEROID-INDUCED PSYCHOSIS AFTER EUS-GUIDED CELIAC PLEXUS BLOCKADE. ACG CASE REP J.. 2017;4:E11", "literaturereference_normalized": "steroid induced psychosis after eus guided celiac plexus blockade", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170302", "receivedate": "20170302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13288263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "Salivary duct carcinoma is a malignant salivary neoplasm with a poor prognosis. Effective treatment for remote metastases has not been recognized. We report herein on a case of this tumor overexpressing HER2 successfully treated with trastuzumab-based molecular targeted therapy. The patient was a 69-year-old man, who developed remote metastases into the liver and the thoracic vertebra six months after surgery and postoperative irradiation for the primary and nodal lesions. After targeted therapy including paclitaxel and trastuzumab, these metastatic lesions showed rapid and continued regression. After paclitaxel was discontinued due to peripheral neuropathy in the extremities, trastuzumab monotherapy followed without resulting in cardiotoxicity. After three years since development of remote metastases, the patient is doing well without re-progression of the disease.", "affiliations": null, "authors": "Iguchi|Fukuichiro|F|;Taniguchi|Zenchi|Z|;Kusano|Junko|J|;Takahashi|Yuka|Y|;Murai|Norihiko|N|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000068878:Trastuzumab; D017239:Paclitaxel", "country": "Japan", "delete": false, "doi": "10.3950/jibiinkoka.117.1108", "fulltext": null, "fulltext_license": null, "issn_linking": "0030-6622", "issue": "117(8)", "journal": "Nihon Jibiinkoka Gakkai kaiho", "keywords": null, "medline_ta": "Nihon Jibiinkoka Gakkai Kaiho", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D044584:Carcinoma, Ductal; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D018987:Salivary Ducts; D012468:Salivary Gland Neoplasms; D000068878:Trastuzumab", "nlm_unique_id": "7505728", "other_id": null, "pages": "1108-14", "pmc": null, "pmid": "25255650", "pubdate": "2014-08", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of metastatic salivary duct carcinoma successfully treated with trastuzumab-based targeted therapy.", "title_normalized": "a case of metastatic salivary duct carcinoma successfully treated with trastuzumab based targeted therapy" }

[ { "companynumb": "JP-ACCORD-026416", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "075436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2 ON DAY 1, 8, AND 15.?THEN 50 MG/M2 ONCE A WEEK.", "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201010", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCALCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC SALIVARY GLAND CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201010", "drugstartdateformat": "610", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201209" } }, "primarysource": { "literaturereference": "IGUCHI F, TANIGUCHI Z, KUSANO J, TAKAHASHI Y, MURAI N. [A CASE OF METASTATIC SALIVARY DUCT CARCINOMA SUCCESSFULLY TREATED WITH TRASTUZUMAB-BASED TARGETED THERAPY]. NIHON JIBIINKOKA GAKKAI KAIHO. 2014 AUG;117(8):1108-14.", "literaturereference_normalized": "a case of metastatic salivary duct carcinoma successfully treated with trastuzumab based targeted therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141030", "receivedate": "20141030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10553778, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "BACKGROUND\nEncephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10-30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA).\n\n\nMETHODS\nThis is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms.\n\n\nCONCLUSIONS\nThe rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.", "affiliations": "Department of Medical Oncology, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. juliette.hamilton@gmail.com.;Department of Neurophysiology, Tallaght University Hospital, Dublin, Ireland.;Department of Medical Oncology, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.", "authors": "Hamilton|Juliette E|JE|http://orcid.org/0000-0002-9614-6500;Alexander|Michael|M|;Kelleher|Fergal C|FC|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13569-020-00147-3", "fulltext": "\n==== Front\nClin Sarcoma Res\nClin Sarcoma Res\nClinical Sarcoma Research\n2045-3329 BioMed Central London \n\n147\n10.1186/s13569-020-00147-3\nCase Report\nIfosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report\nhttp://orcid.org/0000-0002-9614-6500Hamilton Juliette E. juliette.hamilton@gmail.com 1 Alexander Michael 2 Kelleher Fergal C. 1 1 Department of Medical Oncology, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland \n2 Department of Neurophysiology, Tallaght University Hospital, Dublin, Ireland \n28 11 2020 \n28 11 2020 \n2020 \n10 255 7 2020 20 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nEncephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10–30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA).\n\nCase presentation\nThis is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms.\n\nConclusion\nThe rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.\n\nKeywords\nIfosfamide Encephalopathy Methylene blue Frontal rhythmic intermittent delta activity FIRDAissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIfosfamide (3-[2-chloroethyl]-2-[(2-chloroethyl)-amino] tetrahydro-2H-1, 3,2-oxazaphosphorin-2-oxide) is a chemotherapeutic agent used for a variety of solid organ and haematological malignancies, including in the management of sarcomas [1, 2]. It is a prodrug that is metabolized in the liver into the active alkylating agents by cytochrome P450 enzymes [3]. The alkylating agents produced are 4-hydroxy-ifosfamide and ifosfamide mustard with other resultant products including chloroacetaldehyde and chlorothylamine. Chloroacetaldehyde and chlorothylamine are thought likely to be the major contributing factors in the development of encephalopathy, as they are known to be neurotoxic and are able to penetrate the blood–brain barrier [3, 4]. These metabolites are excreted predominantly by the kidneys [2].\n\nNeurotoxicity can manifest in several ways, including lethargy, agitation, disorientation, confusion, hallucinations, extra-pyramidal signs and seizures [1, 5]. In rare cases, the symptoms can progress to coma, irreversible brain damage and death [1]. These symptoms are thought to develop due to glutaric acid accumulation, which may inhibit mitochondrial respiration [4]. This specific pathway was identified after glutaric acid was found in the urine of patients with congenital glutaric aciduria, a congenital metabolic disorder which results in a lack of the flavoproteins for electron transfer in mitochondrial respiration [6]. This disturbance leads to an increase in intracellular nicotinamide adenine dinucleotide, inhibiting the dehydrogenation and oxidation of chloroacetaldehyde and chlorothylamine [3].\n\nThere are many hypothesised risk factors for the development of ifosfamide-induced encephalopathy. Advanced age, poor performance status, impaired renal and liver function, past history of intracerebral pathology, platinum exposure, malnutrition evidenced by low albumin, higher levels of haemoglobin, concomitant use of aprepitant and lower gastrointestinal and pelvic malignancies [3, 7]. Aprepitant is a CYP 3A4 enzyme inhibitor, and therefore has the potential to increase the levels of chloroacetaldehyde and chlorothylamine [1].\n\nIfosfamide-induced encephalopathy is a clinical diagnosis, with onset within 2 h up to 146 h after the commencement of the ifosfamide infusion [1]. It is graded by severity, with grade 1 encompassing a vague or slightly depressive affect, grade 2 resulting in extensive periods of sleep, restlessness or agitation, grade 3 manifests as stupor, heavy depression or mild hallucinations and grade 4 expressing overt hallucinations, seizures or coma [2, 3].\n\nResolution of symptoms have been observed with the administration of methylene blue. Whilst the exact mechanism of action is unclear, it is felt that it serves as an alternative electron acceptor. This prevents chlorothylamine from inhibiting flavoprotein and so corrects mitochondrial respiration [1]. It also inhibits extra-hepatic monoamine oxidases, preventing the dehydrogenation of aldehydes, including the formation of chloroacetaldehyde [1, 2, 6]. The toxicities of methylene blue include cardiac arrhythmias, coronary vasoconstriction, syncope, hemolytic anemia and anaphylaxis [8].\n\nThiamine has also been used in the management of ifosfamide-induced encephalopathy, specifically because of the similar clinical syndrome of Wernicke’s encephalopathy, and has been found to be effective [2]. Additionally, albumin administration to provide binding sites that are unable to cross the blood brain barrier, and haemodialysis, have been found to be effective [2].\n\nCase presentation\n\nOur patient was a 71 year old woman diagnosed with a high-grade right triceps pleomorphic sarcoma in 2017, which was resected with a wide local excision and treated with adjuvant radiation. A surveillance computed tomography (CT) scan of the thorax showed metastases to the lung and mediastinum in September 2018 and she was treated with 6 cycles of doxorubicin. Progression of disease identified in January 2019 necessitated a change of treatment to ifosfamide and mesna, and she was admitted for each cycle. Re-staging CT scan after 2 cycles demonstrated an interval decrease in the size and number of the multiple pulmonary nodules with one nodule reducing in size from 18 mm down to 6 mm, complete resolution of a 15 mm right para-oesophageal node and no new disease identified.\n\nPast medical history included hypertension, hysterectomy for menorrhagia and appendectomy. Her medications on admission were lercanidipine, losartan, hydrochlorothiazide, potassium supplement, enoxaparin (thrombosis prophylaxis), senna, domperidone, aprepitant, Fortisip Compact Fibre, Procal Shot, multivitamin and evening primrose oil (not administered due to unknown possible drug interactions). She was known to develop a rash with penicillin but had no other allergies.\n\nExamination on admission for cycle 3 was remarkable for oral candidiasis. Routine blood investigations identified potassium 2.7 mmol/l which was replaced with IV and oral potassium and albumin of 32 g/l. She developed nausea after day 2 and had one episode of vomiting.\n\nOn day 3, she was noted to be resting during the morning, however was easily rousable and able to stay awake. Chemotherapy was commenced at midday. Within 4 h, it was noted that she was difficult to rouse. Vital signs were within normal ranges. A blood gas confirmed a potassium of 2.7 mmol/l, but no other abnormality was identified and the pH was uncompensated and in the normal range. An ECG was unremarkable. It was hypothesized that she had developed ifosfamide encephalopathy and an EEG was obtained.\n\nDiscussion\nIn the EEG (Fig. 1) taken while the patient was encephalopathic, one can see the generalized features of periodic discharges, occasional triphasic morphology and intermittent delta activity with background attenuation. In addition to this, there is rhythmic delta activity seen intermittently. Unusually, this EEG demonstrates the unusual and rare finding of frontal intermittent rhythmic delta activity (FIRDA) [9]. FIRDA is a non-specific finding associated with frontal pathologies and has been descried in severe metabolic encephalopathies and in cases with significant mid-line shifts. This is a rarely seen phenomenon and was only identified in one case of a recent study by Gudson et al. [10].Fig. 1 The EEG demonstrating FIRDA\n\n\n\nMethylene blue, 50 mg intravenous (IV) slow push, was administered and there was a remarkable recovery with resolution of the drowsiness within 10 min of administration. On resolution of symptoms, the patient reported that she felt considerably better and that she was aware that she had been drowsy and unable to appropriately rouse herself. Oral thiamine was administered and the patient was admitted to the intensive care unit for monitoring. A further EEG was performed after resolution of symptoms, and all the previous features of encephalopathy were proven to have resolved.\n\nLikely contributing factors to the ifosfamide-induced encephalopathy seen in this patient were her advanced age, low albumin, renal impairment manifesting in deranged electrolytes and the addition of aprepitant to her regimen.\n\nConclusions\nThis case is interesting as it adds to evidence to benefit of methylene blue in the management of ifosfamide-induced encephalopathy, and also demonstrates the rarely observed EEG phenomenon of FIRDA during the ifosfamide-induced encephalopathy.\n\nAbbreviations\nCTComputed tomography\n\nEEGElectroencephalogram\n\nFIRDAFrontal rhythmic intermittent delta activity\n\nIVIntravenous\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors' contributions\nJH wrote the paper. MA provided the EEG that was on record from the event and the commentary on the EEG’s. FK provided guidance on the structure of case and reviewed the final submission. All authors read and approved the final manuscript.\n\nFunding\nNo funding was sought or obtained.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent for publication of all information was obtained in writing from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Richards A Marshall H McQuary A Evaluation of methylene blue, thiamine, and/or albumin in the prevention of ifosfamide-related neurotoxicity J Oncol Pharm Pract 2011 17 4 372 80 10.1177/1078155210385159 20861178 \n2. Kataria PS Kendre PP Patel AA Ifosfamide-induced Encephalopathy Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction J Pharmacol Pharmacother 2017 8 1 38 40 10.4103/jpp.JPP_182_16 28405136 \n3. Liu YL Tsai SH Chang FW Yu MH Ifosfamide-induced encephalopathy in patients with uterine sarcoma Taiwan J Obstet Gynecol 2010 49 1 77 80 10.1016/S1028-4559(10)60014-9 20466298 \n4. Sejourne A Noal S Boone M Bihan C Sassier M Andrejak M Two cases of fatal encephalopathy related to ifosfamide: an adverse role of aprepitant? Case Rep Oncol 2014 7 3 669 72 10.1159/000368184 25408661 \n5. Lo Y Shen LJ Chen WH Dong YH Wu FL Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: a retrospective analysis J Formos Med Assoc 2016 115 9 744 51 10.1016/j.jfma.2015.07.016 26302952 \n6. Pelgrims J De Vos F Van den Brande J Schrijvers D Prove A Vermorken JB Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature Br J Cancer 2000 82 2 291 4 10.1054/bjoc.1999.0917 10646879 \n7. Gharaibeh EZ Telfah M Powers BC Salacz ME Hydration, methylene blue, and thiamine as a prevention regimen for ifosfamide-induced encephalopathy J Oncol Pharm Pract 2019 25 7 1784 6 10.1177/1078155218808361 30348070 \n8. Ginimuge PR Jyothi SD Methylene blue: revisited J Anaesthesiol Clin Pharmacol 2010 180 4 517 20 \n9. Dericioglu N Khasiyev F Arsava EM Topcuoglu MA Frontal Intermittent Rhythmic Delta Activity (FIRDA) in the neurological intensive care: prevalence, determinants, and clinical significance Clin EEG Neurosci 2018 49 4 272 7 10.1177/1550059416688108 28118746 \n10. Gudson AMMR Chen X Clinical and EEG characteristics of ifosfamide-related encephalopathy J Clin Neurophysiol 2019 36 2 150 4 10.1097/WNP.0000000000000539 30694943\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-3329", "issue": "10(1)", "journal": "Clinical sarcoma research", "keywords": "Encephalopathy; Frontal rhythmic intermittent delta activity FIRDA; Ifosfamide; Methylene blue", "medline_ta": "Clin Sarcoma Res", "mesh_terms": null, "nlm_unique_id": "101577890", "other_id": null, "pages": "25", "pmc": null, "pmid": "33292592", "pubdate": "2020-11-28", "publication_types": "D016428:Journal Article", "references": "20861178;21547182;25408661;28118746;30694943;28405136;26302952;30348070;20466298;10646879", "title": "Ifosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report.", "title_normalized": "ifosfamide induced encephalopathy the eeg with frontal intermittent delta activity and rapid resolution with methylene blue a case report" }

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IFOSFAMIDE?INDUCED ENCEPHALOPATHY: THE EEG WITH FRONTAL INTERMITTENT DELTA ACTIVITY, AND RAPID RESOLUTION WITH METHYLENE BLUE: A CASE REPORT. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FORTISIP COMPACT FIBRE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "POTASSIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ROUTINE HEALTH MAINTENANCE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM (UNSPECIFIED)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APREPITANT" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021549", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APREPITANT." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOMPERIDONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOMPERIDONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LERCANIDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SENNA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMINS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMINS (UNSPECIFIED)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT NEOPLASM PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAFLO PRO CAL" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2019" } }, "primarysource": { "literaturereference": "HAMILTON JE, ALEXANDER M, KELLEHER FC. IFOSFAMIDE?INDUCED ENCEPHALOPATHY: THE EEG WITH FRONTAL INTERMITTENT DELTA ACTIVITY, AND RAPID RESOLUTION WITH METHYLENE BLUE: A CASE REPORT. CLIN SARCOMA RES. 2020?10(1)", "literaturereference_normalized": "ifosfamide induced encephalopathy the eeg with frontal intermittent delta activity and rapid resolution with methylene blue a case report", "qualification": "3", "reportercountry": "IE" }, "primarysourcecountry": "IE", "receiptdate": "20210315", "receivedate": "20210315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19009935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients.", "affiliations": "Internal Medicine Department, University of São Paulo State, São Paulo, Brazil.", "authors": "Neves|Precil Diego M M|PD|;Freitas|Fernanda M|FM|;Kojima|Christiane A|CA|;Carmello|Beatriz L|BL|;Bazan|Rodrigo|R|;Barretti|Pasqual|P|;Martin|Luis C|LC|", "chemical_list": "D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin", "country": "Canada", "delete": false, "doi": "10.1111/hdi.12194", "fulltext": null, "fulltext_license": null, "issn_linking": "1492-7535", "issue": "19(1)", "journal": "Hemodialysis international. International Symposium on Home Hemodialysis", "keywords": "Chronic kidney disease; hemodialysis; neurotoxicity; piperacillin/tazobactam", "medline_ta": "Hemodial Int", "mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic", "nlm_unique_id": "101093910", "other_id": null, "pages": "143-5", "pmc": null, "pmid": "25098503", "pubdate": "2015-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: a case report.", "title_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report" }

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PIPERACILLIN/TAZOBACTAM-INDUCED NEUROTOXICITY IN A HEMODIALYSIS PATIENT: A CASE REPORT.. 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PIPERACILLIN/TAZOBACTAM-INDUCED NEUROTOXICITY IN A HEMODIALYSIS PATIENT: A CASE REPORT. HEMODIALYSIS INTERNATIONAL. 2015;19 (1):143-145", "literaturereference_normalized": "piperacillin tazobactam induced neurotoxicity in a hemodialysis patient a case report", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150520", "receivedate": "20150520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11125170, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.\n\n\n\nThe extent of identified changes in CLL cells versus memory B cells from healthy donors was termed \"epigenetic burden\" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed \"relapse changes\" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.\n\n\n\nOverall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.", "affiliations": "Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.;Department of Biology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.;Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.;Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.;Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy.;Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.;Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.;Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece. kostas.stamatopoulos@gmail.com.", "authors": "Tsagiopoulou|Maria|M|;Papakonstantinou|Nikos|N|;Moysiadis|Theodoros|T|;Mansouri|Larry|L|;Ljungström|Viktor|V|;Duran-Ferrer|Martí|M|;Malousi|Andigoni|A|;Queirós|Ana C|AC|;Plevova|Karla|K|;Bhoi|Sujata|S|;Kollia|Panagoula|P|;Oscier|David|D|;Anagnostopoulos|Achilles|A|;Trentin|Livio|L|;Ritgen|Matthias|M|;Pospisilova|Sarka|S|;Stavroyianni|Niki|N|;Ghia|Paolo|P|;Martin-Subero|Jose I|JI|;Pott|Christiane|C|;Rosenquist|Richard|R|;Stamatopoulos|Kostas|K|0000-0001-8529-640X", "chemical_list": "D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine", "country": "Germany", "delete": false, "doi": "10.1186/s13148-019-0783-1", "fulltext": "\n==== Front\nClin EpigeneticsClin EpigeneticsClinical Epigenetics1868-70751868-7083BioMed Central London 78310.1186/s13148-019-0783-1ResearchDNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy Tsagiopoulou Maria 12Papakonstantinou Nikos 1Moysiadis Theodoros 13Mansouri Larry 34Ljungström Viktor 4Duran-Ferrer Martí 5Malousi Andigoni 6Queirós Ana C. 5Plevova Karla 78Bhoi Sujata 4Kollia Panagoula 2Oscier David 9Anagnostopoulos Achilles 10Trentin Livio 11Ritgen Matthias 12Pospisilova Sarka 78Stavroyianni Niki 10Ghia Paolo 13Martin-Subero Jose I. 514Pott Christiane 12Rosenquist Richard 3http://orcid.org/0000-0001-8529-640XStamatopoulos Kostas kostas.stamatopoulos@gmail.com 131 Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001 Thermi, Thessaloniki, GR Greece 2 0000 0001 2155 0800grid.5216.0Department of Biology, National and Kapodistrian University of Athens, Athens, Greece 3 0000 0004 1937 0626grid.4714.6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 4 0000 0004 1936 9457grid.8993.bDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 0000 0004 1937 0247grid.5841.8Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain 6 0000000109457005grid.4793.9Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece 7 0000 0004 0609 2751grid.412554.3Department of Internal Medicine–Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic 8 0000 0001 2194 0956grid.10267.32Central European Institute of Technology, Masaryk University, Brno, Czech Republic 9 0000 0000 9910 8169grid.416098.2Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK 10 0000 0004 0576 574Xgrid.415248.eHematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece 11 0000 0004 1757 3470grid.5608.bDepartment of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy 12 0000 0004 0646 2097grid.412468.dSecond Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 13 0000000417581884grid.18887.3eDivision of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy 14 0000 0000 9601 989Xgrid.425902.8Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 2 12 2019 2 12 2019 2019 11 17724 9 2019 19 11 2019 © The Author(s). 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.\n\nResults\nThe extent of identified changes in CLL cells versus memory B cells from healthy donors was termed “epigenetic burden” (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed “relapse changes” (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.\n\nConclusions\nOverall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.\n\nKeywords\nDNA methylationChemoimmunotherapyCLLMicroarray analysisRelapsehttp://dx.doi.org/10.13039/100008594European Hematology Associationhttp://dx.doi.org/10.13039/501100005010Associazione Italiana per la Ricerca sul Cancro21198http://dx.doi.org/10.13039/501100001823Ministerstvo Školství, Mládeže a TělovýchovyCEITEC2020 LQ1601http://dx.doi.org/10.13039/501100007601Horizon 2020AEGLEGeneral Secretatiat for research and technology of GreeceKRIPISERA-NET TRANSCAN-2 JTC 2014, GCH-CLL143MIUR-PRIN2015ZMRFEASwedish Cancer SocietySwedish Cancer SocietyKnut och Alice Wallenbergs Stiftelse (SE)Knut och Alice Wallenbergs Stiftelse (SE)Swedish Research CouncilSwedish Research Councilhttp://dx.doi.org/10.13039/501100007232Radiumhemmets ForskningsfonderRadiumhemmets ForskningsfonderLion’s Cancer Research FoundationLion’s Cancer Research FoundationMarcus Borgström’s FoundatioMarcus Borgström’s FoundatioSelander’s FoundationSelander’s FoundationState of scholarships foundation of GreecefellowshipTsagiopoulou Maria issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMounting evidence highlights a significant contribution of DNA methylation in the onset and evolution of CLL [1]. To large extent, the CLL methylome shares common features with the normal B cell differentiation program [2, 3]. As a whole, CLL cells resemble memory B cells, exhibiting great similarity with the DNA methylation programming for high-maturity memory B cells [3]. Against the initial view that the DNA methylome remains relatively stable, more recent evidence indicates that DNA methylation may evolve overtime, also with respect to treatment [2, 4, 5]. Indeed, patients with mutated IGHV genes (M-CLL) who experience stable disease also display stable DNA methylation patterns overtime, along with limited genetic changes [2]. In contrast, patients with unmutated IGHV genes (U-CLL) appear to show a more wide variation in DNA methylation changes over time [2, 4] along with the appearance of subclones with different genetic aberrations [4]. Despite this evidence, however, the epigenomic contribution to CLL progression remains to be conclusively defined.\n\nThe fludarabine-cyclophosphamide-rituximab (FCR) regimen is a standard treatment option for medically fit CLL patients, excepting those who carry aberrations of the TP53 gene [mutation and/or del(17p)] [6–9]. In fact, along with the somatic hypermutation status of the clonotypic IGHV genes, they are the main predictors of response to FCR treatment in CLL [7–9]. Although FCR is effective with overall response rates in the range of 90%, most patients will eventually relapse with those relapsing within 2 years after FCR experiencing a particularly aggressive disease (“ultra high risk”) [10, 11]. These observations point to a characteristic resistance of the malignant cells that is still not fully characterized from the epigenetic perspective and cannot be reliably predicted, at least for cases not falling in any of the risk categories defined by genetic or immunogenetic biomarkers.\n\nIn the present study, we analyzed the DNA methylomes in longitudinal pre-treatment and post-relapse samples of 34 CLL patients treated with chemoimmunotherapy in order to address if changes occur overtime in relation to therapy. We report that DNA methylation profiles are modulated during CLL evolution, particularly in response to treatment, involving several transcription factors and displaying association with particular genetic aberrations. Moreover, we evaluated the DNA methylation alterations occuring during neoplastic expansion, the so-called “epigenetic burden,” comparing the pre-treatment profiles per case with those of memory B cells from healthy donors and highlight that the EB clusters in specific genomic regions and chromatin states, including regulatory regions contaning binding sites of transcription factors implicated in B cell and CLL biology.\n\nResults\nGenome-wide profiling reveals significant heterogeneity of DNA methylation evolution in CLL\nWe assessed 68 paired samples from 34 CLL cases who received chemoimmunotherapy as first-line treatment: Of these, 31 were treated with the FCR regimen whereas one each of the remaining 3 cases received FC (fludarabine-cyclophosphamide), FCMR (fludarabine-cyclophosphamide-rituximab+mitoxantrone), or BR (bendamustine-rituximab) (Additional file 1: Table S1). Data from 20/34 pre-treatment CLL samples have been previously reported by our group [12]. The time-span between the two examined states (pre-treatment/post-relapse) ranged from 0.75 to 10.9 years with a median of 2.5 years (Table 1). The vast majority of cases concerned U-CLL (29/34, 85.2%), which are associated with adverse prognosis and significantly higher incidence of progressive disease requiring treatment. First, we performed unsupervised hierarchical clustering based on the methylation levels of 451,756 CpG sites across all samples: This analysis did not discriminate the pre-treatment samples from the post-relapse ones (Additional file 2: Figure S1). Next, we performed differential methylation analysis (DMA) at cohort level (|db| ≥ 0.3, p < 0.05 or |db| ≥ 0.3, FDR < 0.05), comparing all the pre-treatment versus all the post-relapse samples, again not identifying differentially methylated CpG (DMCpG) sites.\nTable 1 Clinical data and results of the intra-individual DNA methylation analysis\n\nPatient ID\tU-CLL\tIGHV gene\tAge at diagnosis\tFirst-line treatment\tTreatment response\tTTFT\tTTR\tCytogenetic alterations*\tPearson R\n(MBC vs pre-treatment)\tEpigenetic burden\tPearson R\n(pre-treatment vs relapse)\tRelapse changes\t\nP1\tNO\tIGHV3-11\t48\tFCR\tPR\t1.6\t4.7\tNone\t0.93\t32,380\t0.99\t117\t\nP2\tND\tIGHV1-f\t61\tFCR\tCR\t1.1\t2.6\tdel(13q)\t0.92\t33,441\t0.96\t20,440\t\nP3\tYES\tIGHV3-33\t55\tFCR\tCR\t0.1\t2.3\tNone\t0.93\t34,285\t0.82\t81,383\t\nP4\tYES\tIGHV1-69\t60\tFCR\tCR\t4.3\t5.5\tTrisomy 12\t0.93\t35,098\t0.98\t8052\t\nP5\tYES\tIGVH1-69\t60\tFCR\tPR\t1.4\t1.4\tdel(13q)\t0.92\t36,696\t0.98\t3430\t\nP6\tYES\tIGHV3-33\t52\tFCR\tCR\t4.1\t6.4\tdel(13q)\t0.92\t37,146\t0.99\t3441\t\nP7\tYES\tIGHV4-39\t62\tFCR\tCR\t2.2\t3.6\tdel(11q), del(13q)\t0.92\t37,465\t0.89\t58,299\t\nP8\tYES\tIGHV1-69\t46\tFCR\tPR\t0.3\t1.7\tdel(11q)\t0.92\t38,023\t0.99\t1514\t\nP9\tYES\tIGHV4-31\t64\tFCR\tCR\t4.1\t3.8\tNone\t0.91\t38,652\t0.92\t40,706\t\nP10\tYES\tIGHV1-69\t61\tFCR\tCR\t1.2\t2.2\tdel(11q)\t0.91\t39,164\t0.97\t8199\t\nP11\tYES\tND\t56\tBR\tCR\t2\t3.9\tdel(13q)\t0.92\t39,658\t1.00\t45\t\nP12\tYES\tIGHV5-a\t73\tFCR\tCR\t0.2\t3.8\tND\t0.92\t40,403\t0.87\t60,970\t\nP13\tYES\tIGHV3-20\t49\tFCΜR\tPR\t2.5\t4.1\tTrisomy 12\t0.91\t40,669\t0.99\t511\t\nP14\tYES\tND\t29\tFCR\tPR\t1.5\t4.8\tdel(11q), del(13q)\t0.91\t40,755\t0.99\t1263\t\nP15\tYES\tIGHV1-69\t66\tFCR\tCR\t3.4\t0.9\tdel(11q), del(13q)\t0.91\t41,333\t0.99\t261\t\nP16\tYES\tIGHV4-34\t44\tFCR\tCR\t2.7\t1.4\tdel(11q)\t0.91\t41,399\t0.99\t392\t\nP17\tYES\tND\t36\tFCR\tCR\t2.2\t5.0\tNone\t0.90\t41,875\t0.98\t3150\t\nP18\tYES\tIGHV3-64\t26\tFCR\tCR\t0.9\t1.3\tdel(17p)\t0.91\t42,313\t0.99\t949\t\nP19\tNO\tIGHV1-69\t48\tFCR\tCR\t6.1\t1.8\tdel(13q)\t0.92\t42,384\t1.00\t45\t\nP20\tYES\tIGHV1-69\t61\tFCR\tND\t0\t1.1\tdel(6q)\t0.91\t42,543\t0.99\t457\t\nP21\tYES\tIGHV1-24\t59\tFCR\tCR\t0\t1.2\tNone\t0.91\t42,615\t0.99\t907\t\nP22\tYES\tIGHV3-30\t56\tFCR\tCR\t0\t0.8\tdel(11q)\t0.91\t42,721\t0.99\t287\t\nP23\tYES\tIGHV1-69\t54\tFCR\tCR\t1.5\t0.9\tdel(11q), del(13q)\t0.90\t44,283\t0.99\t90\t\nP24\tNO\tIGHV1-69\tND\tFCR\tCR\t4.7\t1.2\tdel(11q , del(13q)\t0.91\t45,253\t1.00\t45\t\nP25\tYES\tIGHV3-48\t65\tFCR\tCR\t2\t8.0\tdel(13q)\t0.91\t45,372\t0.99\t905\t\nP26\tYES\tIGHV1-69\t64\tFCR\tCR\t0.1\t2.2\tdel(11q)\t0.89\t45,383\t0.98\t4689\t\nP27\tND\tIGHV3-53\t43\tFCR\tCR\t0.1\t10.9\tTrisomy 12\t0.89\t45,999\t0.96\t10,449\t\nP28\tYES\tIGVH3B\t61\tFCR\tCR\t0.1\t1.4\tdel(17p)\t0.90\t46,314\t0.89\t51,925\t\nP29\tYES\tIGHV4-34\t53\tFCR\tCR\t0\t7.9\tNone\t0.90\t50,072\t0.98\t8546\t\nP30\tYES\tND\t55\tFC\tCR\t2\t3.0\tdel(11q)\t0.89\t50,443\t0.98\t2740\t\nP31\tYES\tIGVH3B\t50\tFCR\tCR\t0.1\t1.5\tdel(13q)\t0.89\t52,336\t1.00\t57\t\nP32\tYES\tIGHV3-48\t70\tFCR\tCR\t0.2\t5.1\tdel(11q)\t0.89\t53,793\t0.98\t4504\t\nP33\tYES\tIGVH3A-3B\t59\tFCR\tCR\t0\t2.1\tdel(6q)\t0.86\t59,041\t0.97\t6584\t\nP34\tYES\tIGHV1-3\t38\tFCR\tPR\t1\t3.0\tdel(13q)\t0.89\t60,526\t0.98\t2985\t\nTTFT time to first treatment (years) TTR time to relapse (years), ND not determined. *Detected by karyotype and/or FISH (pre-treatment state)\n\n\n\nNext, we proceeded to methylation analysis at the individual case level. In addition to the DNA methylation changes observed after relapse, we also investigated the alterations which had occurred in comparison to normal B cells. We used as reference available data from two samples of peripheral blood memory B cells (MBC) from healthy donors recently reported by our group [12]. We found high correlation between the biological replicates (Pearson R = 0.99) of MBCs; thus, we merged and used them as a single reference sample.\n\nFirst, we compared the MBC versus the pre-treatment sample for each CLL case and noticed a variability in the Pearson R values ranging from 0.864 to 0.930: The number of DMCpGs (|db| ≥ 0.3), referred to as epigenetic burden (EB), ranged from 32,380 to 60,526 (Fig. 1a–c) (Table 1, Additional file 1: Table S1). All 34 CLL cases showed massive hypomethylation compared to MBC, in keeping with previous reports [13, 14] (Additional file 2: Figure S2).\nFig. 1 Intra-individual DNA methylation analysis reveals significant variability of epigenetic burden and relapse changes between CLL cases. a Dot plots showing the Pearson coefficient values (x-axis) representing the correlation of the MBC with the pre-treatment b values (left part, dark blue) and the correlation of the pre-treatment with the relapse b values (right part, light blue) of each CLL case (n = 34). b Density heatmaps displaying the frequencies of the b values for four selected CLL cases which showed the minimum and maximum Pearson R value after comparison of the b values of MBC (y-axis) and the pre-treatment state (x axis) which are depicted in (i) and (ii), and the b values of the relapse (y-axis) and pre-treatment state, which are depicted in (iii) and (iv). c Barplot, with each bar representing a different CLL case and showing the total number of DMCpGs related to the epigenetic burden (dark blue) plus the total number of DMCpGs related to relapse (light blue). d Barplots showing the percentage of hypermethylated (red color) and hypomethylated (green color) CpG sites at the relapse compared to the pre-treatment state, herein defined as relapse changes (RC), for all cases analyzed (upper part). The barplots in the lower part show the total number of the RCs for each case. Bars represent individual CLL cases\n\n\n\nNext, we compared the pre-treatment sample versus the relapse sample for each case and observed that the number of DMCpGs (|db| ≥ 0.3), referred to as relapse changes (RC), showed significant variability among patients ranging from 45 to 81,383 (Pearson R 0.822–0.996) (Fig. 1a–c) (Table 1, Additional file 1: Table S1). Twenty-three of the 34 (68%) samples after relapse showed a higher number of hypomethylated than hypermethylated CpGs compared to the pre-treatment state (Fig. 1d).\n\nInterestingly, we observed an overlap between the EB and RC, with the number of overlapping CpGs ranging from 13 to 22,853. Next, in order to examine the persistence of specific CpG sites affected at relapse, we calculated the number of overlapping CpGs/RC (Additional file 2: Figure S3). We found that most cases showed > 20% overlap between RC and EB at relapse, implying that DNA methylation changes, at least in part, occur in specific regions.\n\nDNA methylation changes in CLL cluster in specific genomic regions, chromatin states, and transcription factor binding sites\nWe characterized the DMCpGs detected in each CLL case regarding both the EB and the RC based on: (i) their genomic location, (ii) the respective chromatin state of MBC, and (iii) the transcription factor binding sites (TFBS) and performed enrichment analyses in order to gain insight into the biological function of the observed changes. Regarding genomic location and the chromatin state, we observed that the EB-hypomethylated CpGs were enriched in introns, gene bodies, and 3’ UTRs placed mainly in heterochromatin and strong and weak enhancers, while the EB hypermethylated CpGs were enriched in introns and TSS upstream regions (TSS1500) mostly located within polycomb repressed regions, poised and weak promoters, and strong enhancers in all 34 cases (Fig. 2a, c). The RC DMCpGs showed similarities as well as differences from the EB DMCpGs. More specifically, the RC-hypomethylated CpGs showed enrichment in introns, gene bodies, and 3’ UTRs as observed also in EB, but they were placed mainly in heterochromatin with only few cases placed in enhancers. Regarding the RC-hypermethylated CpGs, no consistent pattern was shared between cases. They preferentially clustered to the first exons, introns, and TSS upstream regions, which were located to poised promoters and polycomb-repressed regions, while enhancers were almost absent (Fig. 2b, d).\nFig. 2 Enrichment analysis of the epigenetic burden and relapse changes regarding genomic locations, chromatin states, and transcription factor binding sites. Genomic location enrichment analysis of a the epigenetic burden hypomethylated (green) and hypermethylated (red) CpGs for each CLL case and b the relapse hypomethylated (green) and hypermethylated (red) CpGs for each CLL case. Chromatin states enrichment analysis of c the epigenetic burden hypomethylated (green) and hypermethylated (red) CpGs for each CLL case and d the relapse hypomethylated and hypermethylated (red) CpGs for each CLL case. Each column represents a CLL case, with the cases sorted on x-axis based on the number of DMCpGs per case, from maximum to minimum. Each row represents a genomic element. The red color on heatmap displays the significant enrichment (p < 0.05) in each case for the respective genomic element (ActProm, active promoter; Hete LowSign, heterochromatin low signal; Het Repr, heterochromatin-repressed; PolRepr, polycomb repression; PoisProm, poised promoter; StrEnh1, strong enhancer 1; StrEnh2, strong enhancer 2; Txn_Elong, transcription elongation; Txn_Trans, transcription transition, Wk_Txn, weak transcription; WkEnh, weak enhancer; WkProm, weak promoter. e TFBS analysis of the hypo- and hypermethylated epigenetic burdens and relapse changes revealed significant enrichment for several TFs families (x-axis). The density of heatmap represents the number of patients which showed statistical significant enrichment per TFBS (FDR < 0.05)\n\n\n\nTFBS analysis revealed that both EB- and RC-hypomethylated CpGs were enriched (FDR < 0.05) for binding sites of a large series of TFs (Fig. 2e, Additional file 3: Table S2, and Additional file 4: Table S4). More specifically, in all cases, the EB-hypomethylated regions showed enrichment for several TFs relevant to B cell/CLL biology, including members of AP-1, GATA, IRF, POU, NFAT, STAT, and TCF families, as well as most members of HOX and FOX development-related TFs. This pattern was also observed on RC-hypomethylated regions, albeit in a lower number of analyzed cases (Fig. 2e, Additional file 3: Tables S2 and Additional file 4: Table S4). The EB- and RC-hypermethylated regions showed enrichment for TFBS in fewer CLL cases compared to the EB- and RC-hypomethylated regions, respectively (Fig. 2e, Additional file 5: Table S3, Additional file 6: Table S5 and Additional file 7: Table S6). Both hypo- and hypermethylated regions were enriched for TFBS of HOX and FOX families in contrast to TFBS such as FOS, JUN, IRF, and CEBP, which were specific for hypomethylated regions (Fig. 2e, Additional file 7: Table S6). Interestingly, the RC-hypermethylated regions were enriched for EGR2 and E2F4 binding sites in a large number of CLL cases (n = 14 and n = 18, respectively); however, most analyzed cases did not show similar enrichment for RC-hypomethylated or EB- (both hyper- and hypomethylated) regions (Additional file 7: Table S6).\n\nFinally, KEGG pathway enrichment analysis based on the DM genes, showed that, in almost all cases, EB-hypomethylated and hypermethylated-regions were enriched for pathways significant for CLL biology, e.g., ErbB, Phospholipase D, Ras, HIF, MAPK, Wnt, T, and B cell receptor, and Notch signaling pathways (Additional file 8: Table S7 and Additional file 9: Table S8). In contrast, a similar analysis for RC revealed enrichment in only a fraction of analyzed cases, especially those with a high number of changes, mainly on the hypermethylated gene sets (Chi-squared test, p < 0.05), e.g., pathways in cancer, calcium signaling pathway, and Rap1 signaling pathway (Additional file 9: Table S8).\n\nDNA methylation changes overtime associate with specific biological characteristics and clinical outcome\nBased on the results of the intra-individual methylation analysis, where each CLL case showed a different number of affected CpG sites compared to both the MBC and the relapse state, we explored potential correlations of the EB and RC with clinical and molecular characteristics.\n\nFirst, considering the fact that the DNA methylation profiles are affected by aging [15], we investigated the correlation between the age of patients with EB and RC, however, not finding any significant correlation (Spearman rho between RC and age = − 0.28, p = 0.11 | Spearman rho between EB and age = 0.118 p = 0.50).\n\nNext, we noticed a significant inverse correlation between the EB and the time to first treatment (TTFT) (Spearman rho = − 0.42, p = 0.02) (Fig. 3a); no such correlation was identified with the time-to-relapse (TTR) (Spearman rho = − 0.112, p = 0.52). Moreover, we observed a significant positive correlation between the RC and the TTR (Spearman rho = 0.39, p = 0.02) (Fig. 3b). Relevant to mention, 13 of 34 cases could be characterized as early-relapsing since they relapsed within 2 years of treatment; notably, these cases displayed low or no evolution of DNA methylation. Put differently, we found very few RC in the early-relapsing cases compared to the rest which relapsed after 2 years of treatment, hereafter referred to as the late-relapsing group (median of DMCpGs 39 vs 4689, p = 0.002) (Fig. 3c), which, not unexpectedly, showed significantly longer TTR (median TTRs 1.3 vs 3.9 years, p = 4.32e-11).\nFig. 3 Associations of the epigenetic burden and the relapse changes with clinicobiological characteristics. a Scatter plot showing the epigenetic burden (EB) (y-axis) and the time to first treatment (TTFT) (x-axis) and their correlation coefficients (Spearman rho = 0.42, p = 0.02) for all 34 CLL cases b Scatter plots showing both the relapse changes (RC) (y-axis) and the time to relapse (TTR) (x-axis) and their correlation coefficients (rho = 0.39, p = 0.02) for all 34 CLL cases. The early-relapsing cases are displayed with green and the late-relapsing cases with blue. c Dot plot with median showing the RC of the early-relapsing and late-relapsing groups which show significant differences (p < 0.001). d Kaplan-Meier curves for time to relapse (TTR), with the early-relapsing cases relapse significant earlier than the late-relapsing (Log-test, p < 0.001). e Dot plot with median showing the EB of CLL cases with TP53 and non-TP53 aberrations which display significant differences (p < 0.05). f Columns represent patients (n = 34) and rows genes or cytogenetic abnormalities. The color scale represents the number of DMCpGs from blue (low) to red (high). Regarding cytogenetic abnormalities, black boxes state the presence of the aberration and white boxes the absence. Regarding gene mutations, gray boxes state the existence of whole-exome sequencing (WES) data available for the respective genes and the absence of mutation; gray boxes with asterisk (*) state the presence of mutation detected only at the pre-treatment state, black boxes the presence of mutation at relapse, and black boxes with asterisk represent the presence of mutation detected both at pre-treatment and at relapse state. White boxes state no availability of WES data. ND, not available data; **p < 0.01, *p < 0.05\n\n\n\nNext, we examined potential associations of epigenetic evolution regarding the EB and RC with particular biological characteristics of the malignant clones. Considering that the vast majority of cases (29/34, 85.2%) concerned U-CLL, we did not explore associations with immunogenetic features [i.e., the IGHV gene somatic hypermutation status] and, instead, decided to focus on genomic aberrations. To this end, we used available cytogenetic data (FISH and/or karyotype) regarding the Dohner model abnormalities [i.e., del(11q), del(13q), del(17q), and trisomy 12] for all 34 cases. Moreover, we used existing whole-exome sequencing (WES) data for 26/34 cases reported in a recent publication from our group [16] and examined potential associations with mutations within the ATM, BIRC3, EGR2, MGA, NFKBIE, NOTCH1, SF3B1, and TP53 genes. Additionally, for 16/26 cases, we had available data for clonal evolution (all mutations were documented at both pretreatment and relapse and assigned to separate clusters using the SciClone25 clustering tool). Interestingly, cases carrying TP53 aberrations showed significantly higher EB versus TP53-wildtype CLL cases (median-EB = 45,848.5 vs 42,384, respectively, p = 0.0176) (Fig. 3d). Additionally, most cases with available data (14/16), previously published [16], showed relapse-specific subclones/clusters which expanded significantly to become the dominant clone at relapse; the remaining 2 cases showing a more stable intraclonal composition over time accompanied by no epigenetic evolution after relapse (RC = 117 and 1263). Relevant to mention, the cases analyzed in our study were treated with FCR at a time when signaling inhibitors, currently considered as the standard of care for TP53 aberrant cases, were not available; hence, a proportion of cases who received FCR treatment carried such aberrations. All the examined prognostic markers are summarized graphically in Fig. 3e while the analysis regarding their association with the EB and RC is depicted in Additional file 2: Figures S4-S5.\n\nDiscussion\nRecent studies have demonstrated extensive genetic heterogeneity underlying clonal evolution in CLL patients with adverse clinical outcomes [16, 17]. Besides genetic events, however, CLL is also characterized by epigenetic alterations, with DNA methylation profiles being the best studied thus far [2, 14, 18–20]. Interestingly, a recent study demonstrated that CLL cases belonging to the memory B-cell-like epigenetic subgroup [21] showed a favorable response to FCR [22]. However, insight into how the epigenetic mechanisms might be implicated in disease evolution, particularly the response to treatment, is still lagging.\n\nIn order to obtain evidence regarding this issue, we analyzed longitudinal samples from a series of 34 CLL patients mostly (n = 31) treated with the FCR regimen in order to explore DNA methylation changes overtime and whether these may be associated with the patterns of clinical response. At cohort level, we did not observe recurrent DNA methylation changes, in line with two previous studies [2, 4]. This could be attributed, at least in part, to the large heterogeneity characterizing the DNA methylation profile of CLL cases [23, 24], even those carrying IGHV genes with concordant somatic hypermutation status [12] as in the present series, where the vast majority of cases concerned U-CLL.\n\nConsidering the above, we focused on each individual patient separately and examined both the epigenetic burder (EB), i.e., the methylation changes that tumor cells acquire compared to memory B cells form healthy donors (considering that all CLL cases globally resemble memory B cells) [3] but also the changes between the pre-treatment sample versus the relapse sample, referred to as relapse changes (RC). This intra-individual analysis confirmed once again the pronounced biological heterogeneity of CLL, since great variability was noted between cases regarding both the EB but also the RC. In all cases, CLL cells were characterized by extensive epigenetic reprogramming displaying massive hypomethylation compared to memory B cells, in keeping with previous studies [3, 14, 25]. Relevant to mention, it was recently shown that the number of epigenetic changes that a tumor acquires compared to its cellular origin, i.e., the EB, may be a powerful predictor of clinical aggressiveness in mantle cell lymphoma (MCL) [26] where patients with high EB experienced a worse clinical outcome. Following the same approach, we here report a similar observation also for CLL, since we found that the higher the EB the shorter the TTFT.\n\nRegarding the RCs, we found very high inter-patient variability; some cases had stable epigenetic profiles while others showed significant epigenetic evolution after relapse, with a mixed pattern of hypomethylated or hypermethylated events at relapse. Notably, the number of RCs was positively correlated with the time to relapse. Especially, those cases relapsing within 2 years of treatment (“early-relapsing”) displayed low or no evolution of DNA methylation. Our observation appears to contradict a recent publication [4], which reported that epigenetic evolution after treatment is linked with short time to post-therapy events (treatment and death). These discrepant results might be attributed to differences in the composition and size of the respective study cohorts (21 vs 34 cases in our series) as well as the administered treatments (purine analogs and/or alkylating agents vs FCR in our series), but also differences in the applied data analysis strategies.\n\nIn an attempt to identify a unifying line of events, we sought for connections regarding the methylation changes occurring overtime and also explored associations with genomic alterations and other clinicobiological features. Our results suggest that most CLL cases carrying TP53 aberrations display higher EB compared to the rest and confirm the association of higher EB with shorter TTFT. This finding links adverse-prognostic genomic aberrations with a higher propensity to evolve epigenetically, perhaps as a consequence of high rates of proliferation [27–29]. Such epigenetic evolution might potentially facilitate subclonal expansion as also suggested by a previous study which showed that a high level of alterations in DNA methylation was accompanied with a greater probability to develop new subclones [23]. Admittedly, one could also argue for the opposite, namely that the genomic evolution should fuel the epigenomic evolution, especially considering the well-known complex interplay between genetics and epigenetics whereby the genomic instability could influence the epigenetic evolution and vice versa [30, 31]. Relevant to mention in this respect, p53 gain of function mutants have been found to bind to and upregulate chromatin regulatory genes that may influence the DNA methylation patterns [32]. Turning to RC, we observed significant correlation with TTR but also great heterogeneity. Most early-relapsing cases showed low or no evolution of the respective DNA methylation profiles suggesting that these cases did not have sufficient time to accumulate DNA methylation changes and/or were more progressive. In such cases, treatment with FCR does not appear to impact significantly on the clonal behavior, leading to the re-emergence of a clone that is not fundamentally different from the pre-treatment clone, at least at the level of resolution of our study.\n\nFrom a qualitative point of view, the majority of methylation changes at relapse appear to follow a pattern where hypomethylation events cluster mainly in gene bodies and heterochromatic regions while hypermethylation events cluster in promoters and polycomb-related regions. This pattern is also observed during B cell differentiation (e.g., long-lived memory/plasma cells) as well as in other tumors and may represent a passive result of, e.g., proliferation history and cellular longevity [14, 25, 33]. Relevant to mention, in a previous study from our group, we found that the histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), is upregulated during the disease course in CLL, especially at relapse [34]. In another recent study, Smith and colleagues [5] identified modest recurrent DNA methylation changes during CLL progression in CpG sites enriched for regions near targets of the PRC2 complex.\n\nSubstantial evidence supports an interplay between transcription factors and DNA methylation both during normal B cell development but also during the course of CLL [3, 14, 25]. In the present study, we observed that genomic regions which became hypomethylated prior to treatment initiation but also after relapse were enriched for binding sites of several transcription factor families relevant to B cell/CLL biology, including the GATA, STAT, HOX, and FOX transcription factors (TFs). Among others, we also observed AP-1, POU, and IRF which were descripted to target hypomethylated regions during normal B cell maturation [3] and also the NFAT family which has been associated with hypomethylated regions in CLL [3, 35]. Interestingly, de novo active chromatin regions in CLL compared to normal B cells were very recently reported to be enriched in FOX TF family binding sites as well as the NFAT and TCF/LEF TFs [36]. On the other hand, EGR2 and E2F4 were found to be specifically associated with regions hypermethylated at relapse, implying a direct connection with the relapse mechanism. Of note, EGR2 mutations have been detected in clinically aggressive CLL subgroups [37] while E2F4, a key regulator of the cell cycle, has been reported deregulated in both Burkitt lymphoma and diffuse large B cell lymphoma [38].\n\nConclusions\nIn conclusion, this study highlights that DNA methylation profiles are modulated during CLL evolution, particularly in response to chemoimmunotherapy with the FCR regimen. These distinct dynamics of DNA methylation were linked to clinicobiological characteristics, including genomic aberrations, time-to-first-treatment, and response to treatment as assessed by time-to-relapse. These alterations mainly occurred in specific genomic regions, following a pattern similar to that observed in long-lived memory/plasma cells and other tumor types, while they were associated with binding sites of transcription factors implicated in B cell and CLL biology.\n\nMethods\nPatient samples\nEighty peripheral blood (PB) samples from 40 CLL patients from 7 collaborating institutions in the Czech Republic, Germany, Greece, Italy, Sweden, and the UK were included in the study. All cases were diagnosed with CLL according to the guidelines of the International Workshop Chronic Lymphocytic Leukemia/National Cancer Institute (iwCLL/NCI) [39]. The first sample for each patient was collected before the first treatment and is characterized as the pre-treatment sample while the second soon after clinically documented relapse and is characterized as the post-treatment (i.e., after relapse) sample. Thirty-six of the 40 patients were treated with FCR, 2/40 with FC, and one each of the remaining 2 cases with BR or FCMR. The study was approved by the local Ethics Review Committee of the participating institutions. Demographic, clinical, and biological data for the patient cohort is listed in Additional file 1: Table S1.\n\nCell separation\nThe tumor load of CLL PB samples ranged from 51 to 100%. Purified CLL cell samples (n = 46) were prepared with negative selection of CD19+ B cells from whole blood using the RosetteSep B-cell enrichment kit (StemCell Technologies, Vancouver, BC, Canada) following the manufacturer’s instructions.\n\nDNA methylation array analysis\nPreparation of DNA samples and processing the DNA methylation signal of the Infinium HumanMethylation 450K BeadChip were performed in R using the “minfi” package. We used the subset-quantile within array normalization (SWAN) [40] that corrects for the technical differences between the Infinium I and II assay designs and produces a smoother overall beta value distribution. Moreover, we developed and optimized an analysis pipeline with several filters (i.e., discarding CpGs with low detection p values, sex-specific CpGs, CpGs showing individual-specific methylation, and CpGs overlapping with SNPs). Regarding batch effects, we analyzed 10 patient samples in two different batches in order to check the Pearson R for each sample between the two batches (Pearson R ranging from 0.9932 to 0.9970). Moreover, the in silico purification was performed based on a new approach we previously developed for deconvolution of the DNA methylation signal of mixed subpopulations helping to isolate in silico the DNA methylation levels of the tumor cells [26, 41] (Additional file 2: Figure S6). It is widely acknowledged that CLL cells resemble antigen-experienced B cells, particularly displaying a phenotype more similar to that of memory B cells [42]. Therefore, using memory B cells as a normal counterpart to detect epigenetic changes in CLL patients appears to represent a rational, in fact perhaps the most appropriate, healthy control. With this in mind, we used as reference for normal B cells two samples of peripheral blood memory B cells (MBC) from healthy donors recently reported by our group [12].\n\nData availability\nThe dataset supporting the conclusions of this article is available in the ΕΒΙ repository, https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7575, reference number E-MTAB-7575.\n\nGenomic and functional annotation of CpGs\nThe differentially methylated CpG sites (DMCpGs) were characterized based on their genomic locations (e.g., TSS, exon, and intron) and the chromatin states (ChIP-seq for 6 histone marks) from a pool of memory B cells obtained from healthy male donors with age ranging from 56 to 62 years recently published [26] (the above reference for the functional annotation is age-matched with the present study group with a mean age 56.5 years). Moreover, we investigated the overlap between the DMCpGs and the JASPAR database of transcription factor binding sites [43] (Additional file 2: Supplementary Methods). Finally, we performed KEGG-pathway enrichment analysis using the differentially methylated genes.\n\nStatistical analysis and visualization\nDifferential methylation analysis (DMA) was performed for the CpG sites of methylation profiles between two conditions. CpG sites were considered as differentially methylated when the following criteria were met, specifically, a minimum absolute difference of 0.3 between mean beta-values (beta difference, db) of the two subgroups and a p value criterion when appropriate. We used the Wilcoxon-paired test for paired samples applying FDR for the correction. The Kruskal test was used in a different context for testing differences between independent samples. Data analysis was carried out in the R environment (3.5.1 version). More details can be found in the Additional file 2: Supplementary Methods.\n\nSupplementary information\n\nAdditional file 1: Table S1. Clinicobiological data and results of the intra-individual DNA methylation analysis for the patient cohort.\n\n \nAdditional file 2: Supplementary Methods. Figure S1. A. Hierarchical clustering of all 68 samples, based on the methylation levels of 451756 CpG sites analyzed per case. 30/34 cases showed strong intra-individual similarity. B. Principal component analysis showing components 1 and 2 in the pre treatment and post relapse stage based on 451756 CpG sites. Figure S2. Barplots showing the percentage of hypermethylated (red color) and hypomethylated (green color) CpG sites revealed after the comparison of the MBC (memory B cells) with the pre-treatment state of each case analyzed. Figure S3. Dot plots with median showing the RC in subgroups of CLL cases based on the genomic aberrations. Figure S4. Dot plots with median showing the EB in subgroups of CLL cases based on the genomic aberrations. Figure S5. Dot plots with median showing the RC in subgroups of CLL cases based on the genomic aberrations. Figure S6. Graphical description of the study aim, the study group and the methods used. We performed deconvolution of DNA methylation data, since a part of CLL samples was characterized bythe tumor load <95%. Estimation of the proportion of hematopoietic cell subpopulations in CLL samples and sorted B cells, CD8+ T cells, CD4+ T cells, natural killer cells, monocytes and granulocytes. Sorted cell subpopulations (a right part of the heatmap) are correctly predicted and CLL cases show a gradient from lower to higher proportion of B cells (a left part of the heatmap).\n\n \nAdditional file 3: Table S2. TFBS enrichment analysis of the hypomethylated epigenetic burdens revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 4: Table S4. TFBS enrichment analysis of the hypomethylated relapse changes revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 5: Table S3. TFBS enrichment analysis of the hypermethylated epigenetic burden revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 6: Table S5. TFBS enrichment analysis of the hypermethylated relapse changes revealed common TFs among CLL cases. Each row represents a TFBS and each column represents a CLL case and displays the number of DMCpGs associated with the TFBS. Each patient column is accompanied by one more column representing the p-value after FDR correction regarding the statistical significance according the background. The last column shows the frequency of the enriched cases in each TF. The patients were sorted based on the number of the relapse changes, beggining from the higher to lowest number.\n\n \nAdditional file 7: Table S6. TFBS enrichment analysis of the hypo- and hypermethylated epigenetic burdens and relapse changes separately, revealed common TFs among CLL cases.\n\n \nAdditional file 8: Table S7. KEGG enrichment analysis of the epigenetic burden hypo- and hyper- methylated genes separately, revealed common pathways among CLL cases.\n\n \nAdditional file 9: Table S8. KEGG enrichment analysis of the relapse hypo- and hyper- methylated genes separately, revealed common pathways among CLL cases.\n\n \n\n\nAbbreviations\nBRBendamustine-rituximab\n\nCLLChronic lymphocytic leukemia\n\nDMADifferential methylation analysis\n\nDMCpGsDifferentially methylated CpG sites\n\nEBEgenetic burden\n\nFCFludarabine-cyclophosphamide\n\nFCMRFludarabine-cyclophosphamide-rituximab+mitoxantrone\n\nFCRFludarabine-cyclophosphamide-rituximab\n\niwCLL/NCIInternational Workshop Chronic Lymphocytic Leukemia/National Cancer Institute\n\nMBCMemory B cells\n\nM-CLLChronic lymphocytic leukemia cases carrying mutated immunoglobulin receptors\n\nPBPeripheral blood\n\nRCRelapse changes\n\nTFBSTranscription factor binding sites\n\nTTFTTime-to-first-treatment\n\nTTRTime-to-relapse\n\nU-CLLChronic lymphocytic leukemia cases carrying unmutated immunoglobulin receptors\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nMaria Tsagiopoulou and Nikos Papakonstantinou contributed equally to this work.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s13148-019-0783-1.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nMT performed the study and wrote the manuscript; NP designed the research, performed the study and wrote the manuscript; TM performed data and statistical analysis and assisted in data interpretation; LM, VL, MD-F, AM, NC, ACQ., KP, SB, PK, DP, SL, MG and AH assisted in research, data analysis, and interpretation; DO, AA, LT, MR, SP, NS and PG, provided patient samples; JIMS assisted in data interpretation and revised the manuscript; CP designed research, provided materials and patient samples; RR provided materials, patient samples and revised the manuscript; KS designed and supervised the research and wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported in part by the Horizon 2020 project AEGLE funded by the European Union; the KRIPIS action, funded by the General Secretariat for Research and Technology of Greece; the Ministry of Health of the Czech Republic for conceptual development of research organization FNBr 65269705 and the project CEITEC2020 LQ1601 from the Ministry of Education, Youth and Sports of the Czech Republic; by Associazione Italiana per la Ricerca sul Cancro AIRC (5 per mille Research Program on Metastasis # 21198), Milano, Italy; ERA-NET TRANSCAN-2 JTC 2014, GCH-CLL #143; MIUR-PRIN 2015ZMRFEA, Roma, Italy; the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, Radiumhemmets Forskningsfonder, Stockholm, Lion’s Cancer Research Foundation, Uppsala, Marcus Borgström’s Foundation, Uppsala, and Selander’s Foundation, Uppsala.\n\nMT is a recipient of a fellowship from the State Scholarships Foundation of Greece; and a short-term collaboration award by the European Haematology Association.\n\nAvailability of data and materials\nThe dataset(s) supporting the conclusions of this article is(are) available in the ΕΒΙ repository, https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7575, reference number E-MTAB-7575.\n\nEthics approval and consent to participate\nThe study was approved by the local Ethics Review Committee for the Institute of Applied Biosciences/Centre for Research and Technology Hellas (Ref. No: ETH.COM-45).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nPG has received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. Has received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Novartis, and Sunesis. RR has received honoraria from AbbVie, Janssen, Illumina, and Roche. KS received research support from Janssen Pharmaceuticals and Roche SA. All other authors declare no competing interests.\n==== Refs\nReferences\n1. Mansouri L Wierzbinska JA Plass C Rosenquist R Epigenetic deregulation in chronic lymphocytic leukemia: clinical and biological impact Semin Cancer Biol 2018 51 1 11 10.1016/j.semcancer.2018.02.001 29427646 \n2. 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Young E Noerenberg D Mansouri L Ljungstrom V Frick M Sutton LA EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia Leukemia. 2017 31 7 1547 1554 10.1038/leu.2016.359 27890934 \n38. Molina-Privado I Jimenez PR Montes-Moreno S Chiodo Y Rodriguez-Martinez M Sanchez-Verde L E2F4 plays a key role in Burkitt lymphoma tumorigenesis Leukemia. 2012 26 10 2277 2285 10.1038/leu.2012.99 22475873 \n39. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018.\n40. Maksimovic J Gordon L Oshlack A SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips Genome Biol 2012 13 6 R44 10.1186/gb-2012-13-6-r44 22703947 \n41. Duran-Ferrer M Beekman R Martin-Subero JI In silico deconvolution and purification of cancer epigenomes Oncoscience. 2017 4 3-4 25 26 28540331 \n42. Klein U Tu Y Stolovitzky GA Mattioli M Cattoretti G Husson H Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells J Exp Med 2001 194 11 1625 1638 10.1084/jem.194.11.1625 11733577 \n43. Khan A Fornes O Stigliani A Gheorghe M Castro-Mondragon JA van der Lee R JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework Nucleic Acids Res 2018 46 D1 D260 D2D6 10.1093/nar/gkx1126 29140473\n\n", "fulltext_license": "CC BY", "issn_linking": "1868-7075", "issue": "11(1)", "journal": "Clinical epigenetics", "keywords": "CLL; Chemoimmunotherapy; DNA methylation; Microarray analysis; Relapse", "medline_ta": "Clin Epigenetics", "mesh_terms": "D000328:Adult; D000368:Aged; D003520:Cyclophosphamide; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine", "nlm_unique_id": "101516977", "other_id": null, "pages": "177", "pmc": null, "pmid": "31791414", "pubdate": "2019-12-02", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "22475873;26053498;27191993;22394601;19897574;29140473;21927626;26065654;24138928;26331536;20888994;11733577;26486789;26492934;24465226;22534504;21239840;28921505;29099488;28540331;23064414;24356097;28851627;29540348;27846393;29427646;25151957;30447004;22922567;25860294;26276669;26780610;1382719;23154584;26691213;27890934;31434681;23908595;26675346;25490447;29785028;22703947;23415222", "title": "DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy.", "title_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy" }

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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. 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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200519", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17260988, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "GR-ROCHE-2516774", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17262836, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516395", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS. 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265236, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515870", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS. 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17260986, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516425", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17261916, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516787", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11 (1):177-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17261466, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515911", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17260989, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2519002", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L,LJUNGSTROM V, DURAN-FERRER M ET AL DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS. 2019?11(1):177-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516953", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268102, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515153", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M, ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11(1):177-88.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17271162, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515896", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "M T, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L ,LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(1):177-177.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17261322, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516902", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11(1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17263000, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516765", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):177-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17274980, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516411", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(177):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265290, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2517979", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "M T, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. CLINICAL EPIGENETICS 2019?11 (1):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200116", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17275355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2516747", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. 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DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(1):177-188.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200113", "receivedate": "20200113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17262831, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2515916", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11:1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200521", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17271161, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "GR-ROCHE-2515858", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1)::177.-.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17271191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2514644", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M, ET AL.. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS. 2019?11(1):177-188.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200114", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17265343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-MYLANLABS-2020M1019344", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078980", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V, DURAN-FERRER M ET AL... DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. .. CLINICAL EPIGENETICS. 2019?11(1):1-12", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200225", "receivedate": "20200225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17457463, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "GR-ROCHE-2612734", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE PHOSPHATE." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chronic lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TSAGIOPOULOU M, PAPAKONSTANTINOU N, MOYSIADIS T, MANSOURI L, LJUNGSTROM V ET AL. DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY.. CLINICAL EPIGENETICS 2019?11(177):1-12.", "literaturereference_normalized": "dna methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200603", "receivedate": "20200603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17853183, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "In this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.", "affiliations": "Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel, Switzerland.;Regional Pharmacovigilance Centre Basel, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.;Swissmedic, Schweizerisches Heilmittelinstitut, Bern, Switzerland.;Division of Internal Medicine, University Hospital Basel, Switzerland.;Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland.", "authors": "Istampoulouoglou|Ioanna|I|;Zimmermanns|Barbara|B|;Grandinetti|Tanja|T|;Marzolini|Catia|C|;Harings-Kaim|Annette|A|;Koechlin-Lemke|Sarah|S|;Scholz|Irene|I|;Bassetti|Stefano|S|;Leuppi-Taegtmeyer|Anne B|AB|", "chemical_list": null, "country": "Qatar", "delete": false, "doi": "10.21542/gcsp.2021.11", "fulltext": "\n==== Front\nGlob Cardiol Sci Pract\nGlob Cardiol Sci Pract\nGCSP\nGCSP\nGlobal Cardiology Science & Practice\n2305-7823\nMagdi Yacoub Heart Foundation UK\n\ngcsp.2021.11\n10.21542/gcsp.2021.11\nPharmacovigilance\nCardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre\nIstampoulouoglou Ioanna 16§\nZimmermanns Barbara 126§\nGrandinetti Tanja 16\nMarzolini Catia 36\nHarings-Kaim Annette 26\nKoechlin-Lemke Sarah 126\nScholz Irene 4\nBassetti Stefano 56\nLeuppi-Taegtmeyer Anne B 126anne.leuppi-taegtmeyer@usb.ch\n\n1 Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland\n2 Regional Pharmacovigilance Centre Basel, University Hospital Basel, Switzerland\n3 Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel, Switzerland\n4 Swissmedic, Schweizerisches Heilmittelinstitut, Bern, Switzerland\n5 Division of Internal Medicine, University Hospital Basel, Switzerland\n6 University of Basel, Basel, Switzerland\n§ shared first authorship.\n\n30 6 2021\n30 6 2021\n2021 2 e20211111 4 2021\n31 5 2021\nCopyright ©2021 The Author(s)\n2021\nThe Author(s), licensee Magdi Yacoub Institute.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.\nIn this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.\n==== Body\nIntroduction\n\nThe antiretroviral drugs lopinavir/ritonavir (LPV/r) and the antimalaria drug hydroxychloroquine (HCQ) were initially proposed as potential treatments of COVID-19. Based on currently available data, the benefit-risk profile of these drugs cannot be considered favourable because they did not demonstrate efficacy and there are concerns about their safety1. Prolongation of the QTc interval and the associated increased risk of sudden cardiac death are the most serious adverse reactions2,3.\n\nWith the exception of a few recommendations4, no official guidelines currently exist for handling the risk of drug-induced QTc time prolongation in clinical practice, or for monitoring the QTc interval during therapy with QTc-prolonging drugs. Therefore, management is not uniform and differs among institutions and practitioners. In addition to a baseline ECG, some doctors perform an additional ECG check after the first dose when the maximum plasma concentration of the relevant drug has been reached, while others carry out a further ECG check only after the steady state of the relevant drug has been reached.\n\nAdditionally, it is known, that COVID-19 itself can affect the cardiovascular system and that viral infections predispose patients to cardiac arrhythmia due to metabolic dysfunction, myocardial inflammation and activation of the sympathetic nervous system. Consequently, the development of cardiac arrhythmia in COVID-19 patients is increased2,3,6.\n\nIn this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with LPV/r and HCQ. The cases were reported to our regional pharmacovigilance centre in April 2020. There, pharmacovigilance assessments according to the World Health Organisation (WHO) criteria were performed8.\n\nA spontaneous pharmacovigilance report is a snapshot that provides information on whether a drug or vaccine could in principle be associated with a suspected adverse effect. It also assesses the degree of association between the drug and the suspected adverse drug reaction (ADR), namely as certain, likely, possible, unlikely or unclassifiable. It must be noted that a spontaneous report cannot answer the question whether the symptoms observed in a particular patient are wholly attributable to the drug intake. This question can only be answered by an individual medical opinion. Nevertheless, in Switzerland, medical professionals and all those who manufacture, administer or dispense therapeutic medicinal products – including medical personnel who are authorised to do so – are obliged by law to report the occurrence of ADRs to the national regulatory authority for medicinal products, Swissmedic.\n\nCase presentations\n\nThe relevant demographic, clinical, and laboratory information for each patient case and details about each adverse drug reaction (ADR) as well as the outcome and ultimate pharmacovigilance assessment are given in Table 1.\n\n10.7717/gcsp.202111/table-1 Table 1 Demographic, clinical, and laboratory characteristics of the clinical cases and ADR details.\n\nPatient number\tAge/Sex\tCOVID-19 diagnosis\tComorbidities\tSuspected drugs\tADR\tLatency to ADR\tIntervention\tQTc-maximum values (latency time)\tWHO causality assessment8\tADR outcome at time of PV report\t\n1.\t80-year-old male\tBilateral pneumonia & severe ARDS\t1–2, 6\tLPV/r, HCQ LPV-trough level 26.9 mg/l (day 3 of combination therapy)\tQTc time prolongation from baseline value of 417 msec\tDay 3 of combination therapy\tLPV/r and HCQ stopped after 3 days of combination therapy\t500 msec (5 days after triple combination therapy-stop)\tPossible for all drugs, alone or in combination\tRecovered without sequelae\t\n2.\t82-year-old male\tEnteritis, bilateral pneumonia & severe ARDS\t1–5\tErythromycin, LPV/r, HCQ LPV-trough level 30.1 mg/l (day 3 of LPV/r therapy)\tQTc time prolongation from baseline value of 416 msec\tDay 2 of erythromycin Day 9 of LPV/r 9 days after end of HCQ\tErythromycin and LPV/r stopped after 2 & 9 days of therapy, respectively\t570 msec (1 day after stopping erythromycin- & LPV/r and 10 days after stopping HCQ)\tPossible for all drugs, alone or in combination\tRecovered without sequelae\t\n3.\t77-year-old male\tPneumonia\t1, 5, 7–11\tLPV/r, HCQ LPV-trough level 27.0 mg/l (day 2 of LPV/r therapy) & 20.6 mg/l (day 5 of LPV/r therapy)\tQTc time prolongation from baseline value of 419 msec\tDay 1 of combination therapy\tLPV/r and HCQ stopped after 6 & 3 days of therapy, respectively\t535 msec (day 1 of triple combination therapy)\tPossible for all drugs, alone or in combination\tRecovering\t\nNotes.\n\nADR: adverse drug reaction, HCQ: hydroxychloroquine (800 mg on day 1–2 and 400 mg on day 3), LPV/r: lopinavir/ritonavir (on day 1: 2 × 800/200 mg, then 2 × 400/100 mg/day for 2, 7 or 5 days in cases 1, 2 & 3 respectively), PV: pharmacovigilance, WHO: World Health Organization.\n\nComorbidities: 1. Arterial hypertension, 2. Type 2 diabetes mellitus, 3. Hypertriglyceridemia, 4. Obesity 5. Previous stroke, 6. Previous nephrectomy (normal creatinine value), 7. Chronic renal impairment, 8. Liver cirrhosis, 9. Cardiomyopathy with pacemaker implantation, 10. Recurrent acute polyarticular gout attacks, 11. Lumbovertebral pain syndrome.\n\nAll three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received an off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.\n\nThe first case relates to an 80-year-old male patient hospitalized with bilateral pneumonia and severe ARDS due to a COVID-19 infection, for whom a combination therapy with LPV/r and HCQ was initiated nine days after the initial symptoms developed. Two days later, significant QTc time prolongation was observed and so LPV/r and HCQ were stopped. An intervention for the ECG changes was not necessary. Patients were continuously assessed for arrhythmias, which did not occur in any cases. The QTc time was monitored using 12-lead ECGs and returned to normal within two weeks. The patient recovered from COVID-19 and could be transferred to rehabilitation. His treatment also included tocilizumab and amoxicillin/clavulanic acid, which were not judged to be associated with the QTc time prolongation.\n\nThe second case was an 82-year-old male patient hospitalized with enteritis, bilateral pneumonia and severe ARDS due to COVID-19 infection. He developed QTc time prolongation, which was attributed by his treating doctor as drug induced. Suspected drugs were LPV/r, HCQ and erythromycin. Other causes or risk factors for QTc time prolongation such as underlying cardiac disease or hypokalemia in the context of COVID-19 associated enteritis were not reported. Therapy with LPV/r was terminated 1 day earlier than planned; and so was the therapy with erythromycin. The therapy with HCQ had already ended before the development of the ADR. As far as can be determined, no cardiac arrhythmias occurred and the QTc time returned to baseline.\n\nThe third case refers to a 77-year-old male patient hospitalized with underlying cardiomyopathy (VDD-pacemaker – i.e., ventricle paced, atrium and ventricle sensed – in situ), initially admitted with suspected atypical pneumonia. During the course of the admission the patient was diagnosed with COVID-19 pneumonia and non-invasive ventilation was necessary. The patient was sufficiently oxygenated with 4–6 liters oxygen/min via an oxygen mask. A prolonged QTc time was observed on the same day that therapy with LPV/r and HCQ was initiated. HCQ was continued for two more days and LPV/r for five more days. There were no reports of arrhythmia and the patient made a complete recovery, despite requiring a period of haemodialysis for acute renal failure of multifactorial origin.\n\nPharmacovigilance discussion\n\nLPV/r, HCQ, and erythromycin can all prolong the QTc interval. HCQ and erythromycin are known to cause relevant QTc time prolongation, which according to the latest AHA Recommendations for the Standardization and Interpretation of the Electrocardiogram, is a QTc time ≥ 460 msec in females and ≥ 450 msec in males7; QTc times > 500 msec are generally considered to carry a high risk for torsades de pointes (TdP) arrhythmia15. Although TdP usually ends spontaneously, it can rarely turn into ventricular fibrillation and cardiac arrest with a potentially lethal outcome.\n\nThe mechanism of QTc time prolongation by LPV/r, HCQ and erythromycin is through inhibition of the cardiac hERG (human ether-a-go-go related gene) potassium channels13. Inhibition of hERG channels is largely dose-/concentration-dependent and can be additively increased if hERG blockers are given together13. If QTc time increases by more than 60 msec or over 500 msec, the causative drugs should be discontinued right away14.\n\nThe following cardiac ADRs are described in the drug product information for LPV/r10: as occurring occasionally: atherosclerosis resulting in myocardial infarction, atrioventricular conduction disorder or tricuspid regurgitation. According to post-marketing experience, cases of bradyarrhythmia are also known, but cases of relevant QTc time prolongation, TdP or ventricular fibrillation have not been reported. Based on a controlled, randomized cross-over study in healthy volunteers10 receiving therapeutic doses (400/100 mg LPV/r 2x/day) or supratherapeutic doses (800/200 mg 2x/day), the maximum mean difference (upper limit 95% confidence interval) of the QTc interval with 400/100 mg LPV/r twice daily compared to placebo was 3.6 (6.3) msec; and 13.1 (15.8) msec for supratherapeutic doses of 800/200 mg LPV/r twice daily compared to placebo. QTc time prolongation of ≥ 60 msec from baseline or a QTc in excess of 500 msec did not occur. The product information for LPV/r also points out an increased risk of cardiac complications when combined with drugs known to induce a prolongation of the QTc interval, such as erythromycin or HCQ. According to Eudravigilance data, a QTc time prolongation was described in 17 spontaneous case reports during LPV/r therapy for COVID-193. The global WHO database for reporting ADRs has so far received 25 reports of QTc time prolongation and 7 cases of TdP ventricular arrhythmia following LPV/r therapy out of a total 12,313 reports since 200116. Overall 1,996 ADRs were reported in association with LPV/r in 2020 compared to 424 in 2019 (approximately a 5-fold increase), consistent with widespread use of this drug during the COVID-19 pandemic16.\n\nECG changes are labelled as occasional ADRs in the product information for HCQ11. There are warnings that HCQ may increase the QTc interval in patients with specific clinical risk factors (e.g., heart disease, cardiac arrhythmias, hypokalemia, hypomagnesemia) and when there is simultaneous treatment with substances which also prolong the QTc interval. Dose-dependency with regard to the extent to which the QTc interval is prolonged has been described. The dose in this case was the same as that which is used to treat malaria (1 × 800 mg, then 400 mg/day for 2–3 days). The global WHO database for reporting ADRs has so far received 47 reports of QTc time prolongation and 78 reports of torsades de pointes ventricular arrhythmia in association with HCQ therapy, out of a total of 29,487 reports since 196816. Overall ADR-reporting increased 1.6-fold between 2019 and 2020, consistent with widespread use of this drug during the COVID-19 pandemic16.\n\nIn the Swiss product information for erythromycin, a QTc time prolongation is listed as a rare ADR and simultaneous use of drugs that can also lead to a prolongation of the QTc interval is listed as a contraindication12.\n\nLPV is highly metabolized by the hepatic cytochrome P450 (CYP450) system, primarily by the isoenzyme CYP3A and ritonavir to a lesser extent additionally by CYP2D6. Ritonavir, a potent inhibitor of CYP3A, inhibits the metabolism of LPV, leading to an increase in plasma levels of LPV (so-called “pharmaco-enhancement”). The effective half-life of LPV in this combination is 5–6 hours (steady state is reached after 25–30 hours). The half-life of ritonavir is 3–5 hours (steady state reached after 15–25 hours) so that in theory, concentration-dependent ADRs related to LPV/r can be observed as early as during the first two days of therapy and cease within a few hours to a few days after drug discontinuation. The target LPV trough level at steady state (before the 5th administration) was > 10 mg/l for the treatment of SARS-CoV-2 with LPV/r at the centre which reported the cases. All patients reported here had LPV trough levels exceeding this target, in keeping with the observation by Marzolini and colleagues, that LPV trough levels are approximately 3.5 times higher in patients with COVID-19 compared to patients with HIV infection5.\n\nLPV/r are predominantly metabolized and eliminated via the liver, so that increased plasma concentrations and increased liver toxicity are to be expected in patients with liver dysfunction. As COVID-19 can cause liver dysfunction, this might be one explanation for the reduced LPV clearance observed in these patients9. A more likely explanation for the reduced LPV clearance is COVID-19-associated inflammation, which inhibits drug metabolism, particularly through inhibiting the activity of CYP3A45. Since excretion of LPV via the kidney is negligible, no reduced overall clearance is to be expected in patients with renal insufficiency. At present, there are no data for ritonavir for this specific group of patients.\n\nHCQ is predominantly renally eliminated (69%) and partially metabolized by CYP2C8 and CYP3A4 (see Figure 1)17,18. The elimination kinetics follow a two-compartment model. For this reason, ADRs related to HCQ can in theory occur not only during therapy but also a few days to two months after stopping the drug.\n\n10.7717/gcsp.202111/fig-1 Figure 1. Major pathways of hydroxychloroquine metabolism.\n\nErythromycin is metabolized by the hepatic CYP450 system, primarily by the isoenzyme CYP3A4 and to a lesser extent by CYP2B6. Moreover, erythromycin is a moderate inhibitor of CYP3A4. It is mainly eliminated via the liver and gallbladder and due to its short plasma half-life of 1–2 hours, ADRs related to erythromycin can happen on the first day of therapy.\n\nThe combination of LPV/r, HCQ and erythromycin is problematic both due to pharmacokinetic and pharmacodynamic drug-drug interactions. Combining HCQ and erythromycin – two known QTc-prolonging drugs – with LPV/r, a drug with potential QTc time prolongation, can result in an additively increased risk of QTc time prolongation and TdP.\n\nRitonavir and erythromycin, which are substrates and inhibitors of CYP3A4 at the same time, inhibit both their metabolism and that of lopinavir, another CYP3A4 substrate, leading to a significant higher plasma level of LPV and erythromycin; and subsequently increased risk of ADR, particularly additive QTc time prolongation. The fact that COVID-19-associated inflammation itself predisposes to cardiac arrhythmia and inhibits the activity of CYP3A4, potentiates the risk of drug induced-QTc prolongation even more as evidenced by the increased reporting of QTc prolongation during the COVID-19 pandemic, particularly among male patients19.\n\nClinical implications for prescribing and monitoring\n\nBefore prescribing QTc-prolonging drugs, not only should the potential risk of QTc time prolongation associated with the proposed drug and of all current co-medication be taken into account, but also patient-related and in part modifiable risk factors.\n\nThese risk factors include the female sex, age > 65 years, structural heart diseases, such as heart failure with low ventricular ejection fraction, left ventricular hypertrophy, and myocardial infarction, an impaired hepatic or renal function, an uncorrected electrolyte disturbance like hypokalemia, hypomagnesemia or hypocalcemia and an untreated hypothyroidism4.\n\nPotassium, magnesium and calcium values, as well as the thyroid function, were not reported in our three patients. However, risk factors included older age, while one (the third) patient also had several relevant comorbidities (i.e., cardiomyopathy, pacemaker, chronic renal insufficiency and liver cirrhosis). Such patients with severe COVID-19 progression and multiple risk factors (heart disease, severe renal and liver impairment) are generally predisposed for an increased ADR rate. In addition, when several QTc-prolonging drugs are administered concurrently, the risk of QTc time prolongation increases even more due to potential drug-drug interactions. Since the QTc time peak can occur with a delay, patients must be closely monitored by ECG after administration of one and especially several QTc-prolonging drugs. In addition to determining the QTc time before the start of therapy, we also recommend further measurements, namely at the time when peak concentration (Cmax) is reached after the first administration of the implicated drug (Tmax) and after pharmacokinetic steady state is attained, so that a relevant QTc time prolongation can be detected early enough. The QTc time should ideally be monitored until the QTc time returns to pre-treatment values.\n\nIn conclusion, we report three cases of marked QTc prolongation episodes in patients with severe COVID-19 who received LPV/r and HCQ and which were registered by our pharmacovigilance centre. The analysis of individual risk factors suggest that these drugs possibly contributed to the risk of cardiovascular complications in our three patients with severe COVID-19. Since then, these repurposed drugs failed to show any benefit in the outcome of COVID-19 and so no longer have a place in treatment.\n==== Refs\nReferences\n\n1. 2021 Repurposed antiviral drugs for Covid-19—Interim WHO solidarity trial results New England Journal of Medicine 384 6 497 511 10.1056/NEJMoa2023184 10.1056/NEJMoa2023184\n2. de Barros CM Almeida CA de F Pereira B Costa KCM Pinheiro FA Maia LDB Trindade CM Garcia RCT Torres LH Diwan S Boralli VB 2020 COVID-19 Pandemic—A narrative review of the potential roles of chloroquine and hydroxychloroquine Pain Physician 23 4S S351 S366 32942793\n3. Osborne V Davies M Lane S Evans A Denyer J Dhanda S Roy D Shakir S 2020 Lopinavir-Ritonavir in the treatment of COVID-19: A dynamic systematic benefit-risk assessment Drug Saf 43 8 809 821 10.1007/s40264-020-00966-9 10.1007/s40264-020-00966-9 32578156\n4. Khatib R Sabir FRN Omari C Pepper C Tayebjee MH 2020 Managing drug-induced QT prolongation in clinical practice Postgraduate Medical Journal 10.1136/postgradmedj-2020-138661 10.1136/postgradmedj-2020-138661\n5. Marzolini C Stader F Stoeckle M Franzeck F Egli A Bassetti S Hollinger A Osthoff M Weisser M Gebhard CE Baettig V Geenen J Khanna N Tschudin-Sutter S Mueller D Hirsch HH Battegay M Sendi P 2020 Effect of systemic inflammatory response to SARS-CoV-2 on lopinavir and hydroxychloroquine plasma concentrations Antimicrob Agents Chemother 64 9 10.1128/AAC.01177-20 10.1128/AAC.01177-20\n6. Guzik TJ Mohiddin SA Dimarco A Patel V Savvatis K Marelli-Berg FM Madhur MS Tomaszewski M Maffia P D’Acquisto F Nicklin SA Marian AJ Nosalski R Murray EC Guzik B Berry C Touyz RM Kreutz R Wang DW Bhella D Sagliocco O Crea F Thomson EC McInnes IB 2020 COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options Cardiovascular Research 116 10 1666 1687 10.1093/cvr/cvaa106 10.1093/cvr/cvaa106 32352535\n7. Rautaharju PM Surawicz B Gettes LS Bailey JJ Childers R Deal BJ Gorgels A Hancock EW Josephson M Kligfield P Kors JA Macfarlane P Mason JW Mirvis DM Okin P Pahlm O Herpen Gvan Wagner GS Wellens H American Heart Association Electrocardiography and Arrhythmias CommitteeCouncil on Clinical CardiologyAmerican College of Cardiology FoundationHeart Rhythm Society 2009 AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology J Am Coll Cardiol 53 11 982 991 10.1016/j.jacc.2008.12.014 10.1016/j.jacc.2008.12.014 19281931\n8. The use of the WHO-UMC system for standardised case causality assessment. https://www.who.int/publications/m/item/WHO-causality-assessment 24 May 2021\n9. Del Zompo F De Siena M Ianiro G Gasbarrini A Pompili M Ponziani FR 2020 Prevalence of liver injury and correlation with clinical outcomes in patients with COVID-19: systematic review with meta-analysis Eur Rev Med Pharmacol Sci 24 24 13072 13088 10.26355/eurrev_202012_24215 10.26355/eurrev_202012_24215 33378061\n10. Product Information Kaletra AbbVie®. AbbVie S.A. Switzerland: Cham; 2020. https://compendium.ch/product/1049807-kaletra-filmtabl-200mg-50mg/mpro 10 December 2020\n11. Product Information Plaquenil Sanofi-Aventis®. Sanofi-Aventis (Suisse) S.A. Switzerland: Vernier/GE; 2019. https://compendium.ch/product/15033-plaquenil-filmtabl-200-mg/mpro#MPro7850 10 December 2020\n12. Product Information Erythrocin®. Recordati S.A. Switzerland: Baar; 2016. https://compendium.ch/product/23053-erythrocin-i-v-trockensub-1000-mg/mpro 10 December 2020\n13. Zequn Z Yujia W Dingding Q Jiangfang L 2021 Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel Eur J Pharmacol 893 173813 10.1016/j.ejphar.2020.173813 10.1016/j.ejphar.2020.173813 33345848\n14. Food and Drug Administration HHS 2005 Drug Administration HHS International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability Notice Fed Regist 70 202 61134 61135 16237860\n15. Yap YG Camm AJ 2003 Drug induced QT prolongation and torsades de pointes Heart 89 11 1363 1372 14594906\n16. VigiBase®, Uppsala Monitoring Centre, Sweden, accessed via VigiAccesTMhttp://www.vigiaccess.org/ 2 February 2021\n17. Rendic S Guengerich FP 2020 Metabolism and interactions of chloroquine and hydroxychloroquine with human cytochrome P450 enzymes and drug transporters Curr Drug Metab 21 14 1127 1135 10.2174/1389200221999201208211537 10.2174/1389200221999201208211537 33292107\n18. Wishart DS Feunang YD Guo AC Lo EJ Marcu A Grant JR Sajed T Johnson D Li C Sayeeda Z Assempour N Iynkkaran I Liu Y Maciejewski A Gale N Wilson A Chin L Cummings R Le D Pon A Knox C Wilson M 2018 DrugBank 5.0: a major update to the DrugBank database for 2018 Nucleic Acids Res 46 D1 D1074 D1082 10.1093/nar/gkx1037 10.1093/nar/gkx1037 29126136\n19. Marzolini C Stader F Leuppi-Taegtmeyer A Stoeckle M Battegay M Sendi P 2020 Sex differences in lopinavir concentrations and occurrence of marked QTc prolongation episodes in patients with COVID-19 Drug Saf 10.1007/s40264-020-01025-z 10.1007/s40264-020-01025-z\n\n", "fulltext_license": "CC BY", "issn_linking": "2305-7823", "issue": "2021(2)", "journal": "Global cardiology science & practice", "keywords": null, "medline_ta": "Glob Cardiol Sci Pract", "mesh_terms": null, "nlm_unique_id": "101613130", "other_id": null, "pages": "e202111", "pmc": null, "pmid": "34285902", "pubdate": "2021-06-30", "publication_types": "D016428:Journal Article; D016454:Review", "references": "32641296;33378061;33292107;33245507;14594906;19281931;29126136;32352535;32578156;33264556;33345848;16237860;32942793;33122341", "title": "Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre.", "title_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR\\RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Istampoulouoglou I, Zimmermanns B, Grandinetti T, Marzolini C, Harings-Kaim A, Koechlin-Lemke S, et al. Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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"drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT 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CARDIOVASCULAR ADVERSE EFFECTS OF LOPINAVIR/RITONAVIR AND HYDROXYCHLOROQUINE IN COVID?19 PATIENTS: CASES FROM A SINGLE PHARMACOVIGILANCE CENTRE. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2021?.", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CH", "receiptdate": "20210726", "receivedate": "20200424", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17705879, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "CH-ABBVIE-20K-151-3392070-00", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 1", "drugenddate": "20200329", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200327", "drugstartdateformat": "102", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAQUENIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021906", "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 1: 2X800/200MG", "drugenddate": "20200331", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200329", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INTRAVENOUS INFUSION", "drugdosagetext": null, "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200406", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 3", "drugenddate": 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200401", "drugstartdateformat": "102", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTEMRA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE,NOT AVA", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAY 2", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLAQUENIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.0GR / 0.25MG", "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200402", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAZOBAC" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021906", "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X400/100 MG/DAY", "drugenddate": "20200407", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200402", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN/CLAVULANIC ACID" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 202003" } }, "primarysource": { "literaturereference": "BASSETTI S, SCHOLZ I, MARZOLINI C, ET.AL.. CARDIOVASCULAR ADVERSE EFFECTS OF LOPINAVIR/RITONAVIR AND HYDROXYCHLOROQUINE IN COVID?19 PATIENTS: CASES FROM A SINGLE PHARMACOVIGILANCE CENTRE. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2021?.", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CH", "receiptdate": "20210724", "receivedate": "20200507", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17758709, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CH-LUPIN PHARMACEUTICALS INC.-2022-06692", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210543", "drugbatchnumb": "Unknown", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK (ON DAY 1 AND 2)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", 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Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. 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"medicinalproduct": "PLAQUENIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200317", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LASIX" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021906", "drugbatchnumb": "NOT AVAILABLE,NOT AVAILABLE", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X400/100 MG/DAY", "drugenddate": "20200319", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20200315", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200314", "drugstartdateformat": "102", "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "SCHOLZ I, MARZOLINI C, GRANDINETTI T, ET.AL.. CARDIOVASCULAR ADVERSE EFFECTS OF LOPINAVIR/RITONAVIR AND HYDROXYCHLOROQUINE IN COVID?19 PATIENTS: CASES FROM A SINGLE PHARMACOVIGILANCE CENTRE. GLOBAL CARDIOLOGY SCIENCE AND PRACTICE. 2020?.", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CH", "receiptdate": "20210726", "receivedate": "20200713", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18012140, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CH-NOVARTISPH-NVSC2022CH098314", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR\\RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Istampoulouoglou I, Zimmermann B, Grandinetti T, Marzolini C, Harings-Kaim A,Koechlin-Lemke S et al.. Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. Global Cardiology Science and Practice. 2021;11:1-7", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20220502", "receivedate": "20220502", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20775425, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" }, { "companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-336099", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X800/200 MG, THEN 2X400/100 MG/DAY FOR 2,7 OR 5 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR\\RITONAVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute respiratory distress syndrome", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPINAVIR\\RITONAVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG ON DAY 1-2", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG ON DAY 3", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute respiratory distress 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute respiratory distress syndrome", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Istampoulouoglou I, Zimmermanns B, Grandinetti T, Marzolini C, Harings-Kaim A, Koechlin-Lemke S, et al. Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre. Glob Cardiol Sci Pract. 2021;(2):11:1-7", "literaturereference_normalized": "cardiovascular adverse effects of lopinavir ritonavir and hydroxychloroquine in covid 19 patients cases from a single pharmacovigilance centre", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20220510", "receivedate": "20220510", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20805371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]